2016-2017 INTERAGENCY COORDINATING COMMITTEE strategic plan for disorder 2016-2017 INTERAGENCY AUTISM COORDINATING COMMITTEE strategic plan for autism spectrum disorder 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

COVER DESIGN Medical Arts Branch, Office of Research Services, National Institutes of Health

COPYRIGHT INFORMATION All material appearing in this report is in the public domain and may be reproduced or copied. A suggested citation follows.

SUGGESTED CITATION Interagency Autism Coordinating Committee (IACC). 2016-2017 Interagency Autism Coordinating Committee Strategic Plan For Autism Spectrum Disorder. October 2017. Retrieved from the U.S. Department of Health and Human Services Interagency Autism Coordinating Committee website: https://iacc.hhs.gov/publications/strategic-plan/2017/.

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TABLE OF CONTENTS

About the IACC...... IV

Introduction ...... V

Overview of Progress on Strategic Plan Objectives ...... IX

2016-2017 Strategic Plan Objectives ...... XII

Question 1: How Can I Recognize the Signs of ASD, and Why is Early Detection So Important? ...... XIV

Question 2: What is the Biology Underlying ASD? ...... 12

Question 3: What Causes ASD, and Can Disabling Aspects of ASD be Prevented or Preempted? ...... 28

Question 4: Which Treatments and Interventions Will Help? ...... 44

Question 5: What Kinds of Services and Supports are Needed to Maximize Quality of Life for People on the Autism Spectrum? ...... 62

Question 6: How Can We Meet the Needs of People with ASD as They Progress into and through Adulthood? ...... 72

Question 7: How Do We Continue to Build, Expand, and Enhance the Infrastructure System to Meet the Needs of the ASD Community? ...... 86

Budget Recommendation ...... 100

Statement on Duplication of Effort ...... 104

Conclusion ...... 106

Interagency Autism Coordinating Committee Member Roster ...... 163

Strategic Plan Working Group Members ...... 167

Office of Autism Research Coordination Staff List ...... 180

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ABOUT THE IACC

The Interagency Autism Coordinating Committee (IACC) is a Federal advisory committee charged with coordinating Federal activities concerning autism spectrum disorder (ASD) and providing advice to the Secretary of Health and Human Services (HHS) on issues related to autism. The Committee was established by Congress under the Children's Health Act of 2000, reconstituted under the (CAA) of 2006, and renewed most recently under the Autism Collaboration, Accountability, Research, Education, and Support (CARES) Act of 2014.

Membership of the Committee includes a wide array of Federal agencies involved in ASD research and services, as well as public stakeholders, including self-advocates, family members of children and adults with ASD, advocates, service providers, and researchers, who represent a variety of perspectives from within the autism community. The IACC membership is composed to ensure that the Committee is equipped to address the wide range of issues and challenges faced by individuals and families affected by autism.

Under the CAA and subsequent authorizations, the IACC is required to (1) develop and annually update a strategic plan for ASD research, (2) develop and annually update a summary of advances in ASD research, and (3) monitor Federal activities related to ASD.

Through these and other activities, the IACC provides guidance to HHS and partners with other Federal departments, Federal agencies, research and advocacy organizations, and the broader autism community to accelerate research and enhance services with the goal of profoundly improving the lives of people with ASD and their families.

For more information about the IACC, see http://www.iacc.hhs.gov.

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INTRODUCTION

The Interagency Autism Coordinating Committee (IACC) members on the Committee, which includes at least two is a Federal advisory committee that advises the Secretary members on the autism spectrum, at least two parents or of Health and Human Services on issues related to legal guardians of individuals with autism, and at least two autism spectrum disorder (ASD). It was established advocacy, services, or research organization representatives. by the Children’s Health Act of 2000 (Public Law 106-310), Several of the members have dual roles as professionals in reconstituted under the Combating Autism Act of 2006 fields related to ASD as well as having personal experience (CAA; Public Law 109-416), and was most recently renewed with ASD. The slate of new and returning IACC members in 2014 under the Autism Collaboration, Accountability, was announced in October 2015 and embodies a wide Research, Education, and Support Act (Autism CARES Act; variety of views, perspectives, and expertise. Public Law 113-157). One of the statutory responsibilities of the IACC under the CAA and subsequent authorizations As in previous years, the IACC Strategic Plan is is the development of a strategic plan for ASD, to be updated organized around seven general topic areas that are annually. The IACC Strategic Plan, first issued in 2009, was represented in the Plan as community-focused questions developed by the IACC – including Federal officials and (e.g., Question 1, “How can I recognize the signs of ASD, public stakeholder members – and each edition has been and why is early detection so important?,” which covers informed by extensive input from researchers, adults on the topic of screening and diagnosis). Each question is the autism spectrum, parents, advocates, and the general assigned a chapter in the Strategic Plan that provides an public. This inclusive process has ensured that the IACC Aspirational Goal, or long-term vision for the question, and Strategic Plan reflects diverse perspectives from across the includes: a description of the state of the field; the needs autism community. The Autism CARES Act requires that the and opportunities in research, services, and policy; and IACC include in the Strategic Plan information concerning, three to four broad objectives for each question topic. “as practicable…services and supports, for individuals with There is also one cross-cutting objective on the topic of an autism spectrum disorder and the families of such ASD in females. individuals,” along with information about ASD research. In this edition, which includes an entirely new set of For the 2016-2017 IACC Strategic Plan, the Committee strategic objectives, the IACC Strategic Plan for Autism agreed that given the recent advances in the autism field, Spectrum Disorder addresses this new requirement by it was an appropriate time to re-evaluate the autism taking a more comprehensive approach that not only landscape and formulate new objectives for each question. addresses autism research, but also incorporates more With access to an extensive portfolio analysis conducted information about gaps, opportunities, and implications by the National Institutes of Health (NIH) Office of related to autism services, supports, and policies. Autism Research Coordination (OARC), as well as the annual IACC Summary of Advances documents from past This 2016-2017 revision of the IACC Strategic Plan is the years, the IACC reviewed what has been invested in ASD work of the IACC membership appointed under the CARES research in the United States since 2008. The 23 new Act. The CARES Act increased the required number of public objectives in this Plan were created by the Committee to

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address critical gaps and potential advances they perceived Research on genetic risk and the underlying basic biology in the current research landscape. Because the objectives of ASD remains a primary focus of the research portfolio have been updated and broadened from the previous and does play an important long-term role in the potential Strategic Plan’s 78 research objectives, the IACC expects to develop new and broadly beneficial therapies and that multiple funder portfolios will play key roles in interventions. These advances may one day mitigate or addressing different aspects of each objective in this Plan. even eliminate some of the most disabling aspects of Furthermore, in light of the wide range of needs in autism autism, especially for those on the spectrum who are most research and services, the IACC recommends doubling severely impacted. However, balanced with the potential the 2015 overall autism research budget level of $343 for long-term efforts to lead to significant future advances million to $685 million by the year 2020. Although this and opportunities is the importance of efforts that can funding would not be sufficient to accomplish all of the have a more immediate impact. Individuals on the autism objectives described in this Plan, it would represent an spectrum today will remain autistic for the foreseeable aggressive step toward progress. future; most of them have significant unmet needs. To help those people – who range in age from infants to In formulating this new Plan for ASD activities, the IACC senior citizens – we must in the short-term translate has moved toward a paradigm shift in how we approach existing research to develop effective tools and strategies autism. A few years ago, scientists saw autism as a disorder to maximize quality of life, and minimize disability, while to be detected, treated, prevented, and cured. The majority also ensuring that individuals on the autism spectrum of research was directed at understanding the genetic and are accepted, included, and integrated in all aspects of biological foundations of autism, and toward early detection community life. and intervention. Today, our understanding of autism is more nuanced. We realize that there are many different The community has been very clear in its calls for more “autisms” – some severe, and some comparatively mild – and research into adult issues and better services and supports that ASD affects several distinct domains of functioning for the millions of Americans living with autism today. differently in each individual. We have come to understand Recent studies of adult mortality have indicated that that autism is far more common than previously suspected people with ASD are at higher risk of premature death than and there are most likely many undiagnosed children, people in the general population, painting a very adolescents, and adults in the population, as well as disturbing picture that bears investigation. In light of data under-identified and underserved individuals and groups, and insights from the community, the IACC proposes a such as girls/women with ASD, people in poorly resourced comprehensive research agenda that addresses the needs settings, members of underserved minority communities, of autistic people across the spectrum and across the and individuals on the autism spectrum with language lifespan, including improvements to services, supports, and/or intellectual disabilities. Most importantly, individuals and policies. The IACC also believes that, as many in on the autism spectrum have become leading voices in the autism community have indicated, efforts to address the conversation about autism, spurring acknowledgment the many co-occurring conditions that accompany autism of the unique qualities that people on the autism should be made a greater priority. spectrum contribute to society and promoting self-direction, awareness, acceptance, and inclusion as important Though this 2016-2017 IACC Strategic Plan for Autism societal goals. Spectrum Disorder cannot possibly capture all the changes in the ASD field since 2008, the IACC has endeavored to deliver an updated picture of the evolving landscape of

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autism, as well as a new, broad vision of the current and describes specific scientific findings that members of the future challenges and opportunities in autism research, IACC identify as having significantly advanced the field services, and policy. To provide a more complete and detailed and as having the potential to impact public health and view of autism research progress, this update accompanies quality of life in the ASD community. Together, with this two other annual IACC publications. The IACC Autism 2016-2017 IACC Strategic Plan for ASD, the Committee Spectrum Disorder Research Portfolio Analysis Report describes hopes that these documents will provide an insightful Federal and non-Federal investments in autism research. overview of the state of autism in 2017, as well as outline The annual IACC Summary of Advances in ASD Research a strategic agenda for future progress.

ViSiON STATEMENT

The IACC Strategic Plan for ASD will accelerate and inspire research, and enhance service provision and access, that will profoundly improve the health and quality of life of every person on the autism spectrum across the lifespan. The Plan will provide a blueprint for ASD research and services efforts, engaging the participation and input of government agencies, private organizations, and the broader autism community.

MiSSiON STATEMENT

The purpose of the Strategic Plan is to focus, coordinate, and accelerate innovative research and foster development of high-quality services in partnership with stakeholders to address the urgent questions and needs of people on the autism spectrum and their families.

CORE VALUES

The IACC adopted the below core values and emphasized their significance to the 2016-2017 Strategic Plan development and implementation:

Sense of Urgency: We will focus on responding rapidly and efficiently to the needs and challenges of people on the autism spectrum and their families.

Excellence: We will pursue innovative scientific research of the highest quality and development and dissemination of evidence-based services and practices to maximize the quality of life for people on the autism spectrum.

Spirit of Collaboration: We will treat others with respect, listen with open minds to the diverse views of people on the autism spectrum and their families, thoughtfully consider community input, and foster discussions where participants can comfortably offer opposing opinions.

Community Focus: We will focus on making a difference in the lives of people affected by ASD, including people with ASD, their families, medical practitioners, educators, and scientists. It is important to consider the impact of research on the quality of life, human rights, and dignity of people with ASD, from prenatal development forward.

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Partnerships in Action: We will value cross-disciplinary approaches, data sharing, teamwork, and partnerships to advance ASD research and service activities.

Equity: We will prioritize improved access to detection, intervention, and other services and supports for individuals with ASD, and commit to the goal of reducing disparities across the lifespan, spectrum of ability and disability, sex and gender, racial and cultural boundaries, socioeconomic status, and geographic location to improve the health and quality of life of all individuals with ASD.

Please note: The terms “person with autism,” “person with ASD,” “autistic person,” and “person on the autism spectrum” are used interchangeably throughout this document. Some members of the autism community prefer one term, while others prefer another. The Committee respects the different opinions within the community on the use of this language and does not intend to endorse any particular preference. In addition, the terms “autism” and “autism spectrum disorder (ASD)” are used interchangeably throughout this document unless otherwise noted.

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OVERVIEW OF PROGRESS ON STRATEGIC PLAN OBJECTIVES

The Interagency Autism Coordinating Committee (IACC) proportions of funding than others due to the activities of launched its first Strategic Plan for Autism Spectrum Disorder the funders included in the analysis. As in previous years, Research in 2009, providing a framework to guide the autism Question 2 (Biology) received the largest portion of funding research efforts of Federal and private funders. The IACC (32%) in 2015, encompassing projects supported by nine Strategic Plan organizes research priorities around seven funders. Research in this field focuses on identifying the general topic areas represented as community-focused biological differences and mechanisms in early development “questions.” The questions are divided further into research and throughout life that contribute to ASD, as well as the objectives that address key research needs, gaps, and characterization of the behavioral and cognitive aspects opportunities identified by the Committee. Prior to the of ASD. Projects ranged from basic neuroscience using 2016-2017 IACC Strategic Plan, the most recent update cellular and animal models to clinical studies. Question 3, to the IACC Strategic Plan’s objectives occurred in 2011, research which aimed at identifying potential causes and leading to a total of 78 objectives for autism research. risk factors for the disorder, had the second largest portion of funding (18%). Question 3 research projects addressed The 2014-2015 IACC ASD Research Portfolio Analysis topics such as identifying genetic that increase Report provides the most recent progress on the previous the risk of autism, developing improved approaches to IACC Strategic Plan objectives. In 2015, significant progress studying environmental exposures and -environment was made toward completing the objectives in the interactions, and exploring the potential roles of the 2011 Strategic Plan, with 97% (76 objectives) of the 78 microbiome and on etiology. Treatments objectives either partially or fully completed – meaning and interventions (Question 4) followed closely with 17% objectives had all or some of the required funded projects. of total funding, which included research on behavioral Considering the period from 2008-2015, only 3% therapies, pharmacological treatments, and technology- (2 objectives) of the 2011 Strategic Plan objectives were based interventions. Research projects in Question 4 not active at any point across this eight-year window. encompass the development of new treatments using This indicates that the vast majority of priority areas model systems and small-scale experiments as well as identified by the IACC were deemed by Federal and private full-scale clinical trials. Investment in research infrastructure research funders to be worthy of investment and were and surveillance (Question 7) had a significant proportion implemented either partially or fully. However, many of funding at 16%. Projects in Question 7 covered data areas of partial funding in autism research initiatives left sharing, workforce development, ASD surveillance, and significant gaps over this period. communication/dissemination of research findings and evidence-based practices. Research to improve screening In 2015, ASD research funding supported projects relevant and diagnosis (Question 1) of ASD was 9% of funding in to all seven questions in the IACC Strategic Plan for ASD 2015. Question 1 objectives focused on research to develop Research. However, some questions received greater biomarkers, screening tools, and diagnostic instruments

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to aid in early identification. Research focused on services While each question’s funding amount varied throughout (Question 5) and lifespan issues (Question 6) remained the eight-year span, the overall ASD funding proportions the smallest areas of funding (6% and 2%, respectively). remained relatively the same from 2008-2015. The Question 5 objectives addressed issues surrounding access underlying biology (Question 2) of ASD, the detection to services, coordination of community-based supports, of risk factors (Question 3), and the development of assessment of health and safety, and improving efficacy, treatments and interventions (Question 4) consistently cost-effectiveness, and dissemination of evidence-based received the greatest investments in research. Research practices. Research projects within Question 6 attempted focused on services (Question 5) and lifespan issues to identify and address gaps in transition to adulthood (Question 6) remained relatively low in funding throughout and long-term outcomes in quality of life for people on the years. Question 2 (Biology) is the only research area the autism spectrum. that received significant increases in funding over most of the time period from 2008-2015.

2008-2015 ASD RESEARCH FUNDING

Question 1 – Diagnosis Question 4 – Interventions Question 6 – Lifespan

Question 2 – Biology Question 5 – Services Question 7 – Infrastructure

Question 3 – Risk Factors Question 5 – Services Estimated

$120,000,000

$100,000,000

$80,000,000

$60,000,000

$40,000,000

$20,000,000

$0 2008 2009 2010 2011 2012 2013 2014 2015

Figure 1. ASD research funding from 2008-2015 by Strategic Plan question area.

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In 2008, the reported autism research funding for Federal and reached many milestones, but have also uncovered agencies and private organizations was $222.2 million and emerging areas in need of investments. While additional 745 projects. In 2015, funding for ASD research among investment is particularly needed in these emerging both Federal and private funders totaled $342.6 million areas of ASD research, an overall increase in funding to and spanned 1,410 research projects. Over the eight years, support the entire autism portfolio will be critical to move autism research showed a general upward trend in funding, the field forward and capitalize on scientific opportunity, increasing by 35% since 2008. Looking over the last eight as is described in the IACC Strategic Plan’s budget years, significant advances have been made in autism recommendation. This new edition of the IACC Strategic research in each of the question areas prioritized by the Plan builds on the priorities established in the previous Committee. But, there are still some areas of research that editions of the Strategic Plan, identifies the gaps in research, lack the support needed to foster significant progress. and provides recommendations for future research and Since the development of the last IACC Strategic Plan, services endeavors so that we continue to make a difference autism researchers have made several important discoveries in the lives of people with ASD and their families.

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2016-2017 STRATEGIC PLAN OBJECTIVES

QUESTION 1 HOW CAN I RECOGNIZE THE SIGNS OF ASD, AND WHY IS EARLY DETECTION SO IMPORTANT?

1 Strengthen the evidence base for the benefits of early detection of ASD. 2 Reduce disparities in early detection and access to services.

Improve/validate existing, or develop new tools, methods, and service delivery models for detecting ASD in order 3 to facilitate timely linkage of individuals with ASD to early, targeted interventions and supports.

CROSS-CUTTING

Support research to understand the underlying biology of sex differences in ASD, possible factors that may be 1 contributing to underdiagnosis, unique challenges that may be faced by girls/women on the autism spectrum, and develop strategies for meeting the needs of this population.

QUESTION 2 WHAT IS THE BIOLOGY UNDERLYING ASD?

1 Foster research to better understand the processes of early development, molecular and neurodevelopmental mechanisms, and circuitry that contribute to the structural and functional basis of ASD.

2 Support research to understand the underlying biology of co-occurring conditions in ASD and to understand the relationship of these conditions to ASD.

3 Support large-scale longitudinal studies that can answer questions about the development of ASD from pregnancy through adulthood and the natural history of ASD across the lifespan.

QUESTION 3 WHAT CAUSES ASD, AND CAN DISABLING ASPECTS OF ASD BE PREVENTED OR PREEMPTED?

Strengthen understanding of genetic risk and resilience factors for ASD across the full diversity and heterogeneity 1 of those with ASD, enabling development of strategies for reducing disability and co-occurring conditions in ASD.

Understand the effects on ASD risk and resilience of individual and multiple exposures in early development, 2 enabling development of strategies for reducing disability and co-occurring conditions in ASD.

Expand knowledge about how multiple environmental and genetic risk and resilience factors interact 3 through specific biological mechanisms to manifest in ASD .

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QUESTION 4 WHICH TREATMENTS AND INTERVENTIONS WILL HELP?

1 Develop and improve pharmacological and medical interventions to address both core symptoms and co-occurring conditions in ASD.

2 Create and improve psychosocial, developmental, and naturalistic interventions for the core symptoms and co-occurring conditions in ASD.

3 Maximize the potential for technologies and development of technology-based interventions to improve the lives of people on the autism spectrum.

QUESTION 5 WHAT KINDS OF SERVICES AND SUPPORTS ARE NEEDED TO MAXIMIZE QUALITY OF LIFE FOR PEOPLE ON THE AUTISM SPECTRUM?

1 Scale up and implement evidence-based interventions in community settings.

2 Reduce disparities in access and in outcomes for underserved populations.

Improve service models to ensure consistency of care across many domains with the goal of maximizing 3 outcomes and improving the value that individuals get from services.

QUESTION 6 HOW CAN WE MEET THE NEEDS OF PEOPLE WITH ASD AS THEY PROGRESS INTO AND THROUGH ADULTHOOD?

Support development and coordination of integrated services to help youth make a successful transition to 1 adulthood and provide supports throughout the lifespan.

Support research and implement approaches to reduce disabling co-occurring physical and mental health conditions 2 in adults with ASD, with the goal of improving safety, reducing premature mortality, and enhancing quality of life.

Support research, services activities, and outreach efforts that facilitate and incorporate acceptance, 3 accommodation, inclusion, independence, and integration of people on the autism spectrum into society.

QUESTION 7 HOW DO WE CONTINUE TO BUILD, EXPAND, AND ENHANCE THE INFRASTRUCTURE SYSTEM TO MEET THE NEEDS OF THE ASD COMMUNITY?

1 Promote growth, integration, and coordination of biorepository infrastructure.

2 Develop, enhance, and link data repositories.

3 Expand and enhance the research and services workforce, and accelerate the pipeline from research to practice.

Strengthen ASD surveillance systems to further understanding of the population of individuals with ASD, 4 while allowing comparisons and linkages across systems as much as possible.

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Aspirational Goal: Provide the earliest possible diagnosis for people on the autism spectrum, so they can be linked to appropriate interventions, services, and supports in as timely a manner as possible to maximize positive outcomes.

INTRODUCTION

Observational studies of infants at risk for ASD reveal behavioral interventions initiated in ASD toddlers within that, although timing of the emergence of ASD features this time period result in a range of positive changes is variable, subtle signs can be detected within the first including increases in social attention, language ability, few years of life. Experienced clinicians who are trained to and overall IQ.3,4,5 However, due to the lag in diagnosis, use validated diagnostic tools can diagnose ASD by 18-24 many children miss the opportunity to receive treatment months of age. Still, most children are not diagnosed in the during this critical period of neuroplasticity. This chapter U.S. until four years of age, with disparities in diagnosis reviews the state of knowledge about screening and related to socioeconomic factors, geographic location, and diagnostic tools, as well as the current state of service race/ethnicity.1 Given the unprecedented growth and delivery and challenges families face when trying to organization of the brain during the first three years of life,2 access screening and diagnostic services.

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IMPLEMENTATION OF ASD SCREENING AND DIAGNOSTIC TOOLS

Although studies consistently report that screening using delay or disability.16 However, administering follow-up validated autism-specific parent-report tools can result in questions in the M-CHAT-R/F procedure can take anywhere ASD detection as young as 12-18 months,6 these tools are from 5 to 30 minutes and as such does not overcome the only used systematically within about 50% of primary care barrier of time limits in primary care settings.14 Leveraging settings.7 Reliance on using a standardized screening tool technology, recent studies have shown that a full has even been shown to be more effective than pediatrician administration of the M-CHAT-R/F on a computer tablet not clinical judgment alone.8 Thus, the American Academy only resulted in greater and more accurate documentation of of Pediatrics (AAP)9 has embraced using universal ASD the screening results within electronic medical record screening10 standardized tools as the gold standard for systems, but also eliminated the time barrier because parents detecting ASD and recognizes screening as a critical service answered the follow-up questions directly on the tablet, need to improve early access to care. Barriers that prevent thus bypassing the need to engage medical personnel.17 widespread uptake of parent-report and other screening tools within primary care settings include: lack of education Large-scale studies examining the M-CHAT1,18 and its and understanding of ASD,11,12 lack of familiarity with revisions16,19,20 compared to the estimated prevalence screeners,11,13 uncertainty about where to send a toddler rates suggest that many cases of ASD may be missed with a test-positive screen,14 lack of effective and timely using the screening tool, especially in 18-month olds. This means of connecting families of individuals with ASD to may be due to many factors, including: the accuracy of available resources,12,15 and the extra time and resources the screening tool, ability of parents to notice and report required to utilize standardized screening tools.14,11 early signs of autism, readiness of parents to act on a positive autism screen, and the heterogeneity in symptom Given that many parents take their child for well-baby visits presentation at this young age, suggesting that screening within a primary care setting, recent research has utilized efforts may need to go beyond simple parent-report tools. this context to improve screening. To accommodate the One such approach is a two-stage screening model that dynamic and busy environment of a primary care setting, combines a general developmental screening tool based parent-report screening tools are designed to be very on parent report, the Infant Toddler Checklist (ITC),21 with brief. A new revision to the Modified Checklist for Autism in subsequent observational ratings to screen for ASD. Using Toddlers, Revised, (M-CHAT-R), the most commonly used this approach, detection rates have been reported as 15.1 parent-report screening tool, shows that with the per 1,000 children at a mean age of 20.8 months,22 which administration of follow-up questions (M-CHAT-R/F), is very close to the expected prevalence rates for ASD.1 50% of children who test positive are later diagnosed with Children identified through the M-CHAT-R/F alone display ASD, and if all developmental delays are also considered, a lower developmental level than children ascertained with then over 95% of children who test positive are diagnosed the ITC and follow-up observational rating,22,23 and a lower with either autism or some other type of developmental developmental level than those evaluated in a prospective

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sample of younger siblings at familial risk for ASD,24 (fMRI) studies of infants are beginning to predict later suggesting that this tool may be better at detecting children ASD diagnosis and core characteristics such as language at a lower developmental level and may sometimes miss outcome.35,36,37,38 Additionally, RNA expression profiles less severely affected children. Continued improvement can classify toddlers with ASD at levels exceeding 80% in screening approaches may be achieved by better accuracy.39 While these findings suggest a future of understanding the psychometric features of parent-report exciting new tools for screening and diagnosis, they must screening tools in relation to observational measures,23,25 be validated in other high-risk groups and in the general and by examining the effectiveness of different screening population, and they must be adjusted for broader use in thresholds in relation to diagnostic accuracy and cost- order to be beneficial to the wider community. effectiveness.26 Additional new innovations in parent-report screening approaches include the incorporation of Although engagement in early treatment has been photographs into the questionnaire to illustrate items in associated with a range of positive changes including a culturally unbiased manner,27 combining multiple increases in social orienting, language ability, and overall 3-5,40 screening tools to improve sensitivity and specificity,28 IQ, no study has directly examined if children with and free mobile applications (apps), such as ASDetect that ASD detected by early screening have better outcomes augment descriptions of ASD characteristics with video than those detected by other means, (e.g., parent or examples and provide a video-led assessment of child provider concern) an issue highlighted by the recent US 10 behaviors. Studies are needed to validate the usability and Preventive Services Task Force (USPSTF) report on accuracy of these apps, although there is empirical universal early screening. However, as noted by Dawson 41 support demonstrating that the markers highlighted within (2016), such a study would require large representative the apps (e.g., pointing and showing) are predictive of samples from across the country to be randomly assigned an ASD diagnosis.29,30 to either a screening or non-screening condition, and then followed to determine long-term outcomes and societal A growing appreciation of ASD as a condition marked by costs. Given that early treatment for children under age 3 unique behavioral, neural, and genetic signatures that may years has been shown to result in positive gains,42 and has precede noticeable clinical symptoms has resulted in even been associated with an increased potential to lose a surge of prodromal and biomarker-seeking research an ASD diagnosis altogether,43 such a study can which broadens the scope of future screening efforts. be controversial. Of particular interest are potential biomarkers likely to facilitate gene-brain-behavior studies, diagnosis, or those While a considerable investment of time and resources that may act as prognostic markers. Observational studies would be required to conduct new randomized controlled continue to reveal that signs of ASD are subtle, but may trial (RCT) studies to specifically address concerns raised emerge within the first year of life, particularly in the by the USPSTF, there are opportunities and study designs areas of social communication, attention, and motor that could be leveraged using existing resources in the development.24,31,32 Preliminary studies deploying eye- short term. First, data could be examined from within sample tracking technology to measure social visual engagement cohorts that include clinical longitudinal data from toddlers have demonstrated utility and accuracy in detecting detected via screening as well as toddlers detected via markers of ASD in the first year of life.33,34 For the first time, other means (e.g., parent or clinician concern). Second, structural and functional magnetic resonance imaging exclusively within cohorts of screen-detected toddlers, researchers could examine outcomes of children detected

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at identical early ages via screening but that contained a In order for screening to be effective, ample evaluation subgroup of toddlers who started treatment well beyond centers must be available with appropriate ASD diagnostic the screen-detected age. In this way, the impact of very expertise. Indeed, uncertainty regarding where to send a early treatment engagement as afforded by screening toddler for an evaluation is a barrier to screening noted by could be more directly examined. In terms of new, future over 75% of pediatricians.14 Therefore, an increase in the studies, in instances where a traditional RCT design number and accessibility of evaluation centers is necessary, (intervention versus no intervention) may not be feasible based on population and expected rates of ASD. Likewise, and the health impact is high, other complex forms of RCT significant enhancement of the screening and evaluation models could be used as well as utilizing administrative system is meaningful only if high-quality treatment data. Several states collect state-level data on youth who providers are available and affordable. Some efforts have receive ASD screening and subsequent developmental been made, such as “Birth to Five: Watch Me Thrive!”, outcomes. This may afford an opportunity to compare which is a coordinated Federal effort to raise awareness children with and without early screening in terms of about the importance of universal early behavioral and variations in developmental outcomes. developmental screening. This resource offers a collection of research-based screening tools for children under the While early detection, whether achieved through universal age of 5. However, there is still a need to investigate more screening or by other mechanisms such as parent or clinician cost-effective modes of treatment delivery, such as those concern, is an essential step in the health care process for that are either partially or fully deployed by parents.3 ASD and deserves more research attention, it is just one step on the path to identification and eventual treatment. An increase in the number of toddlers screened and identified Screening in and of itself does not determine if and when as possible ASD20 also calls for the need to standardize parents actually follow through with subsequent diagnostic policies regarding eligibility for IDEA Part C services, the evaluation and treatment engagement, nor does it determine Federal program that funds intervention services for children the quality and benefits of such treatment. Another key gap in showing delays, including autism, from birth through 2 the field is the lack of studies examining the many important years of age. Generally, toddlers must first qualify for basic factors that follow after screening has occurred.44 Part C services by exhibiting a particular state-mandated level of delay (usually a 25% delay in two or more areas), There is indeed a growing appreciation of the importance which often provides for just a few hours of speech or of implementation science methods to examine contextual occupational therapy. Although autism is an automatic factors (e.g., mode of screening delivery) that may impact eligibility category, a child must be identified as either successful screening uptake. Some studies are currently ASD or showing signs of ASD in a separate evaluation underway, performed by researchers funded through the visit in order to be eligible to receive ASD-specific treatment. National Institute of Mental Health ASD Prevention, Early Currently, there are no guidelines mandating that all Detection, Engagement and Services (ASD-PEDS) Network. toddlers receiving Part C services should be examined for Another important factor is comprehensive tracking of possible ASD. Even once a child is referred for an in-depth treatment participation, which is essential to determine the ASD evaluation, there are no policies regarding specific long-term outcomes of children detected early by screening. diagnostic and other evaluation tools that should be used To date, most studies do not report treatment engagement, to determine if a child is eligible for ASD-specific services. and if it is reported, it is often at a very coarse level Unsurprisingly, many toddlers already receiving Part C (e.g., number of hours).

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services for a developmental delay have not been properly identified in time to receive early intervention. Providing evaluated for ASD. Even more concerning, the vast majority clear guidelines regarding ASD detection and subsequent of toddlers with ASD (at least 75%)45 who will go on to treatment eligibility through Part C will help to eliminate qualify for special education at school-age are still not these deficiencies.

DISPARITIES IN ASD SCREENING AND DIAGNOSIS

DiSPARiTiES iN ASD SCREENiNG In addition to dedicating more resources to early screening in underserved communities, a corresponding increase in The barriers that limit screening during well-child visits funding adequate evidence-based diagnostic evaluations have immediate service access implications for children will avoid lengthening waitlists.54 from diverse backgrounds. Overall, ASD screening rates during primary care visits range from 1-60%;7,13,46 some VALiDiTY OF SCREENiNG iNSTRUMENTS of the variability in use of standardized screening is iN DiVERSE GROUPS based on children’s sociodemographic characteristics. For example, screening may occur less frequently among A number of studies have examined ASD screening Spanish-speaking families compared to English-speaking tools in different languages and cultural settings within 50,55,56,57,58 families.47 Families with low levels of maternal education the US and across the world. The variability of exhibit higher screen positive rates on the M-CHAT(-R);48,49 results from these studies indicate that there is a need but are less likely to follow up with diagnostic evaluation, for additional research to adapt tools that will be valid suggesting that these families are at risk for being under- (i.e., demonstrate adequate sensitivity and specificity) served.50 Additionally, consistent use of screening tools in diverse populations. Factors including low educational may depend on insurance reimbursement; children from attainment, language/literacy, rural versus urban locale, low-income families may be more likely to be screened race, and ethnicity also impact screening reliability and 57 50,58 during check-ups since it is often reimbursed by Medicaid,51 validity as well as screen-positive rates. Studies but may not be covered by private insurance. examining medical or state records for specific mention of ASD screening and diagnosis would be Research has shown that children from minority backgrounds helpful in documenting disparities and also in tracking are diagnosed on average more than a year later than their improvements based on policy changes or improved White peers.52 However, it has been demonstrated that access to care. when physicians follow a standardized screening protocol, 10 including immediate referral for screen-positive cases, The recent USPSTF report on universal ASD screening disparities in age of diagnosis are reduced to approximately specifically highlighted the gaps in research on health 1 month.53 Therefore, access to screening for all children, outcomes of children detected through screening, particularly regardless of sociodemographic characteristics, language in those from minority and low-income families. It will be spoken at home, and geographic locale, is crucial to critical to evaluate the quality of screening instruments reduce existing disparities that impact life-long outcomes. and programs in diverse samples of children, including

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long-term outcomes. Implementation studies examining from early ASD screening to appropriate diagnosis to early the translation from research settings to community settings intervention.66 Finally, and perhaps most importantly, there with diverse populations, including examining fidelity of is a need for prospective studies that demonstrate that adhering to screening protocols, also is a critical gap in equal access to high-quality screening, with immediate the existing literature.58,59,60,61 referral for screen-positive cases to diagnostic evaluation and early intervention services, will reduce disparities in DiSPARiTiES iN ACCESS TO DiAGNOSTiC prevalence, as well as any disparities in long-term outcomes SERViCES AND AGE OF DiAGNOSiS for children with ASD.

Differences both in prevalence rates and age of Practitioner efforts that can help to reduce disparities diagnosis by sociodemographic characteristics likely in diagnosis include increasing psychoeducation to raise relate to disparities in access to expert services. According awareness and reduce stigma, building external to the most recent surveillance study by the Centers for professional networks, promoting continuing education Disease Control and Prevention’s (CDC) Autism and programs, using alternative service delivery models Developmental Disorders Monitoring (ADDM) Network (e.g., telehealth, web-based, community health workers) study,1 White children were 20% more likely to have or settings (e.g., schools, child care centers, mobile clinics) indicators of ASD in their school and health records than for screening/diagnosis, and providing wraparound services Black children, 40% more likely than Asian and Pacific that address additional stresses (e.g., chronic illness, Islander children, and 50% more likely than Latino children. unemployment, lack of insurance) often faced by individuals A variety of factors, including economic challenges,50 in underserved communities. Finally, it is clear that children geographic distance between families and service providers,62 are not often well-tracked from the time of ASD screening reduced professional resources and capacity,63 and to receipt of services.52 It is imperative to have a system characteristics impacted by cultural knowledge, such as in place that can assure children and families adequate, stigma64 often contribute to diminished service availability timely, and appropriate services as they move through and utilization in rural, minority, or other disadvantaged the identification, referral, and treatment process. communities. A primary barrier to ASD early diagnosis is the limited availability of diagnostic clinics with providers VALiDiTY OF DiAGNOSTiC iNSTRUMENTS trained in ASD diagnosis, leading to long waiting lists ACROSS SPECiAL POPULATiONS and poor reimbursement for comprehensive diagnosis.54 This limited availability is especially pronounced in There is general agreement that the best approach resource-poor and rural areas, with many children not to ASD diagnosis includes both parent interview and an 67 diagnosed until entry into the school system. observational assessment of the child, such as the Autism Diagnostic Interview-Revised (ADI-R) and the In addition, family level variables such as insufficient Autism Diagnostic Observation Schedule (ADOS-2). The financial resources, lack of insurance coverage, language ADI-R has been translated into 17 languages, and a small barriers, geographic isolation, and limited knowledge of number of studies have examined the validity of the ADI-R or experience with complex healthcare systems, may be in different countries with varying results.68,69,70,71 With barriers to the timely diagnostic evaluation of an at-risk respect to validation studies with diverse populations in the child.65 Overall, there is limited research that documents US, researchers found that the sensitivity and specificity of these systemic- and individual-level barriers that exist the ADI-R with a US-based Spanish-speaking population

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of parents of children with ASD were lower72 than values the gender differences in ASD, both biological and previously reported for mostly White, middle-class behavioral, in the development of diagnostic tools. Also at respondents.73 The communication domains were found risk of being underdiagnosed are individuals with ASD that to be especially problematic for parents whose primary have other co-occurring developmental conditions. A third language was Spanish when reporting on children who of children with ASD also have an ,1 spoke mainly English.72 Little is known about the validity and many individuals with ASD have a dual diagnosis of of the ADI-R among low-income families in the US. The attention-deficit/hyperactivity disorder (ADHD); having ADOS-2 has been translated into 19 different languages; multiple conditions often leads to a misdiagnosis or a however, cross-cultural validation studies of the ADOS-2 delayed ASD diagnosis.79 While research is necessary to have not been identified. develop tools that account for the overlap in symptomology, health providers must consider multiple diagnoses The development of screening and diagnostic tools has during evaluation. largely been accomplished using data from boys, which might put other underserved populations of ASD at a In addition, increasing numbers of adults are presenting disproportionate risk of not receiving a clinical diagnosis. to clinics for first-time diagnoses of ASD, and recent studies Based on recent literature, there appears to be a diagnostic suggest that many adults with ASD may be unidentified and gender bias, which means that girls are less likely than living in the community without appropriate supports.80,81 boys to meet diagnostic criteria for ASD at comparatively There is a need to improve diagnostic tools that are high levels of autistic-like traits.74,75 Girls may also exhibit specific for adults; this will be discussed in more detail in different symptoms from boys, which may make current Chapter 6: How can we meet the needs of people with screening and diagnostic tools more likely to miss ASD ASD as they progress into and through adulthood? in girls.76,77,78 It is important that future research addresses

WORKFORCE

The increased prevalence of diagnosed ASD cases over this need, CDC, in collaboration with the Health Resources the past two decades has led to a need for a larger workforce and Services Administration (HRSA), developed a web- trained in the identification and diagnosis of these disorders, based education program, the Autism Case Training, to including psychologists, psychiatrists, developmental inform healthcare providers on fundamental components pediatricians, neurologists, and speech and language of identifying, diagnosing, and managing ASD through pathologists. Early detection of ASD will require training real- life scenarios. Promoting, refining, and delivering those professionals who come in regular contact with similar education programs is a critical factor in building young children, including primary care providers and child a workforce that can effectively serve individuals with care providers, to incorporate effective screening and ASD and their families. referrals in their daily practice patterns. In response to

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Evidence demonstrates that healthcare professionals are opportunity to improve the identification of ASD through less likely to detect ASD using developmental surveillance materials prepared in languages spoken by target groups without the use of screening tools. Even experienced within these communities, but even more important are professionals may miss or misjudge symptoms during a brief efforts to implement culturally competent practices and observation.18 However, primary care providers face barriers engage a workforce with greater cultural diversity in order to implementing screening that include the time necessary to better address the needs of culturally diverse populations. to identify ASD, the cost of conducting screening and the For example, outreach activities held in places of worship reimbursement for this work, and having appropriately and other community gatherings where families feel more trained personnel in their offices or referral networks. comfortable may improve parent-provider partnerships Also, practitioners may lack the technical training to review and lead to increased identification of ASD. and compare complex psychometric information on the quality of developmental screening tools. Training for this Some important service initiatives to address screening workforce is needed to improve their ability to screen and diagnosis training are ongoing, but there is a need for effectively, recognize ASD symptoms, communicate clearly additional efforts. The AAP supports universal screening with parents, and refer appropriately for evaluation and for ASD and provides training to pediatric providers through intervention services. several formats (publications, webinars, and face-to-face conferences). Leadership Education in Neurodevelopmental Parents may not recognize signs of developmental delay, and Related Disabilities (LEND) and the University Centers or may have concerns about their child’s development of Excellence in Developmental Disabilities (UCEDDs) but do not know how or when to act on those concerns. also provide training to practitioners from over a dozen There is a need to raise public awareness of the early signs healthcare disciplines. Despite the recommended guidelines of ASD, to encourage parents to observe and track their for utilizing these resources, the professional community child’s development, and to encourage them to discuss is not reaching most of the families and children in need their concerns with their child’s doctor, teachers, and other of early intervention. Therefore, service-relevant policies care providers. The “Learn the Signs. Act Early.” campaign need to make professional development and training more developed by CDC, and the “16 Gestures by 16 Months” available as well as dedicate more resources in order to series developed by the First Words Project are examples expand the workforce to address unmet needs for early of strategies that can be utilized to raise awareness and screening and diagnostic services, including access to care. facilitate parent-provider collaborations. However, there is Furthermore, there is a need for improved policies to still a critical research gap on understanding how parent facilitate the collaboration of community-based programs concerns can impact parent engagement in acting on and social supports with professional services. referral for diagnosis and early intervention.

Addressing gaps in our understanding of how healthcare professionals can best reach families from underserved communities continues to be a challenge. There is an

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LINKAGE TO INTERVENTION SERVICES AND OTHER SUPPORTS

It is critically important that children with ASD are identified issue is that some insurance plans do not cover quality early so they can be referred to intervention programs that treatments, such as applied behavior analysis (ABA), or address their individual needs. Eligibility criteria and the may place limits on essential behavioral, medical, or other lead agency for early intervention vary by state (health healthcare. Additionally, family social service supports, agencies in some states, and child welfare or education which contribute greatly to meeting the needs of the child, agencies in other states). Similarly, some states or regions are not covered. These limitations often leave families have more comprehensive insurance coverage and/or struggling in many ways, which results in significant more coordinated systems of healthcare than others. financial and familial burdens. In fact, nearly half of families Even in better-resourced areas, families are often faced of children with ASD say their child’s health condition has with many complex steps from screening to diagnosis to caused major problems for the family and in some cases treatment. Most infants and toddlers with a diagnosis of bankruptcy and other family disruptions, such as divorce ASD miss the opportunity to receive early intervention or job loss. 83,84 services.45 This service need is unmet to an even greater degree in children from minority backgrounds.52 There is Currently, families must navigate different sectors of service a need to improve access to early screening and to increase in terms of information, provision, and funding (e.g., medical the accuracy of screening tools because these are the providers, local government, education) all within a very gateway to early intervention services. Coordination of a short period of time (from noted concern to early intervention care team that includes healthcare and childcare providers age eligibility cut-offs). The different service sectors are is critical to address gaps in screening, begin to break not coordinated and often do not communicate with each down barriers for families to act on screening results, and other, particularly across health and social service agencies. support family engagement in intervention services. Systematic barriers for families include considerable differences in the type and amount of services supported Nearly half of children with ASD have private insurance; by insurance plans, geographic differences in type and the other half have insurance provided by Medicaid or the amount of services available, and inequities and disparities state-based Children’s Health Insurance Program (CHIP), existing across counties and states. Lastly, systems do or dual private and public coverage.82 However, about half not take into account families’ concerns about stigma, the of families of children with ASD report that their insurance reluctance of professionals to make a diagnosis or share coverage is inadequate to meet their myriad of complex concerns about red flags of ASD in very young children, needs and costs. As noted earlier, reimbursement for ASD missed or false positive diagnoses, and the need for earlier screening may improve screening rates and more readily evaluations and re-evaluations of very early assessments become a standard procedure in practices. A systemic as symptoms are unfolding.

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SUMMARY

Significant advances have been made toward early diverse populations and settings; an insufficient workforce identification of individuals with ASD, so they can be linked with expertise in ASD diagnosis and intervention; lack of to appropriate interventions, services, and supports in as medical home for families of children with ASD; the need for timely a manner as possible. However, gaps still remain. continued insurance reform; disparate and uncoordinated There is a need to validate tools in diverse settings and service sectors; and the lack of an infrastructure to track populations. There is a need to evaluate the effectiveness children and families in order to evaluate the efficacy of universal screening for improving outcomes in ASD. of service systems. There have been important strides There is a great need to understand the disparities in access in the area of early detection of ASD features and in and/or utilization of screening and diagnostic tools, and demonstrating the impact of early intervention. Yet, there entry into intervention services. In addition, research is are significant challenges and barriers to implementing needed to develop, adapt, and validate tools that will enable screening, diagnostic, and treatment services broadly and detection of autism in children with intellectual disabilities, reducing disparities in access and utilization. The way forward girls, and adults. The challenges and barriers include gaps is reflected in the three objectives proposed for Question 1. in the evidence base for the benefits of early detection in

OBJECTIVES

OBJECTiVE 1: Strengthen the evidence base for the benefits of early detection of ASD.

Examples:

• Implement innovative designs to evaluate the benefit of universal screening for ASD, including research that addresses the specific research gaps noted by the USPSTF report.

• Conduct studies focusing on the differences and needs of special populations such as girls and individuals with intellectual disabilities.

OBJECTiVE 2: Reduce disparities in early detection and access to services.

Examples:

• Improve family engagement and help build an awareness of healthy developmental milestones and warning signs of concern.

• Demonstrate the validity of different screening and diagnostic tools for culturally diverse communities.

• Increase services in high-poverty and underserved regions; improve inclusion of these populations in research.

• Address differences in state policy requirements for Medicaid and the requirement of a diagnosis to receive services.

• Develop a culturally competent and more culturally diverse workforce.

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OBJECTiVE 3: Improve/validate existing, or develop new tools, methods, and service delivery models for detecting ASD in order to facilitate timely linkage of individuals with ASD to early, targeted interventions and supports.

Examples:

• Continue research on the potential translation of biomarker findings into feasible and valid screening or diagnostic tools.

• Increase coordination and personalization of screening, diagnosis, and early intervention services through use of the medical home model, person-centered planning, or other service models.

• Conduct research to better understand and develop strategies to address reasons for lack of compliance with screening recommendations; address barriers to universal screening.

• Analyze the impact of insurance reform and national policy on coverage for screening, diagnosis, and intervention for children with ASD and their families.

• Evaluate innovative service delivery methods (e.g., use of technology) to improve detection methods and increase access.

CROSS-CUTTING OBJECTIVE

The topic of girls and women with ASD is mentioned in several chapters of the Strategic Plan, indicating the Committee’s strong interest in this area. To combine the priorities for research and services to understand and better serve the needs of girls on the autism spectrum, this “cross-cutting” objective was developed. Individual projects assigned to this objective will be coded to different questions of the Strategic Plan depending on which aspect of ASD in girls and women is being studied. This will ensure the funding associated with those projects will be counted toward the totals of their respective questions, but also allows the projects to be added together into a single objective. The goal of a single “cross-cutting” objective on girls and women with ASD is to encompass the numerous research and services priorities identified by the Committee throughout the Strategic Plan and allow for this area to be identified as a priority for funders.

CC1. Support research to understand the underlying biology of sex differences in ASD, possible factors that may be contributing to underdiagnosis, unique challenges that may be faced by girls/women on the autism spectrum, and develop strategies for meeting the needs of this population.

Examples:

• Conduct research on the underlying biology of ASD in girls/women (differences in brain structure, function, physiology) and how this may create differences in .

• Identify risk and resilience factors that contribute to sex differences.

• Develop, adapt, or validate screening and diagnostic tools to detect ASD in girls.

• Develop strategies to meet the intervention, service, and support needs of girls/women with ASD.

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Aspirational Goal: Discover how alterations in brain development and the function of physiological systems lead to ASD in order to enable the development of effective, targeted interventions and societal accommodations that improve quality of life for people on the autism spectrum.

INTRODUCTION

Current scientific evidence suggests that ASD results with remodeling of genetic material, changes to ion from subtle alterations during brain development that affect channels (which are the basis for cellular function and brain structure, function, and connectivity. However, our communication), and that regulate cell-to-cell knowledge about its causes remains incomplete and communication. Taken together, this research suggests significant gaps in science have hindered attempts to develop there may be shared features of the underlying biology therapies to improve quality of life for individuals with across the spectrum of autism. However, we currently ASD. Over the course of the last decades, several studies know very little about the precise pathways that cause have revealed the role of prenatal or perinatal stressors the circuit changes driving the core behavioral features and genetic contributors to the risk of developing ASD, in ASD, but new tools promise to accelerate this area of possibly acting through changes in early brain development. investigation. In addition, while there have been recent The biological mechanisms by which known gene mutations gains in understanding ASD developmental trajectories cause syndromic ASD (i.e., the subtypes of ASD that are and the nature and prevalence of co-occurring conditions usually caused by a single genetic abnormality) by altering in persons with ASD, more work is needed to understand the underlying neural circuitry of the brain are under these aspects of ASD and develop strategies to target intense study. These genetic variants are associated them successfully.

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MOLECULAR MECHANISMS AFFECTED BY IMPLICATED IN ASD

Genetic studies of ASD have identified more than allows scientists to study the effects of ASD mutations in 100 high-risk genes and estimate that several hundred human brain cells in addition to commonly used transgenic additional genes of this type will be identified in the future.1 animal models. Furthermore, iPSCs are attractive models It seems likely that over 1,000 genes conferring lower for identifying molecular phenotypes linked to syndromic degrees of autism susceptibility will also be identified in ASD, but a more high-throughput means of identifying and the future.2,3,4,5,6,7 At present, the known functions of validating their relevance to ASD is needed. A strategy for these genes converge on biological processes important identifying relevant molecular phenotypes in iPSCs from for neuronal communication and regulation of the the much more common idiopathic ASD (ASD of unknown expression of genes and proteins. cause) remains a daunting task. In addition, new research may make it possible to grow “brain organoids,” which are The discoveries of gene mutations that cause syndromic clumps of brain tissue partially organized to have some ASD (e.g., tuberous sclerosis complex (TSC), , features of the human brain, from iPSCs. These partially , Phelan McDermid syndrome), and matured “mini-” can be grown in a culture dish and the dozens of rare de novo (spontaneous) mutations that can be used to enable the study of the early development 8 disrupt gene function in ASD have enabled scientists to of brain structures that occurs in utero, as well as the explore the biological effects of the various involved genes cellular and circuit abnormalities related to ASD-linked in cellular and animal experiments. This has led to an mutations.11,12 However, these in vitro studies will introduce explosion of research examining how these mutations alter a number of variables related to culture conditions, and the biology of cells and investigating their effects on neural deliberate actions will be required to evaluate reproducibility. circuitry and behavior. On the horizon are genetic tools that will enable the introduction of mutations into Though new iPSC and brain organoid technologies non-human primates,9,10 which possess a much greater allow for the study of human cells and circuits derived behavioral repertoire and a more human-like brain than from persons with ASD, there is no substitute for careful rodents or other animal models. However, these experiments structural and transcriptomic studies in postmortem will need to be designed carefully because the numbers tissue which remains exceptionally rare. Efforts need to of matched control and mutant animals need to be very be redoubled to increase the accessibility of brain tissue small as compared to rodent studies. from well-characterized ASD cases. The establishment of collaborations like the National Institutes of Health (NIH) A major advance over the last few years is the ability to NeuroBioBank and Autism BrainNet facilitates the take skin or blood cells from persons with ASD, create distribution of high-quality, well-characterized human induced pluripotent stem cells (iPSCs), and differentiate postmortem brain tissue for the research community. these cells into , which can enable the study of neural function at the cellular level. This new technology

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Enhancing efforts to increase public awareness about the (female) extends beyond reproduction-related value of tissue donation for understanding brain disorders functions. Studies have suggested that genes on the sex like autism will most effectively advance the science. chromosomes may act as broad regulators of gene expression. Therefore, differences in gene regulation by Studies of postmortem brain tissue from persons with X-X gene pairs in females versus X-Y gene pairs in males ASD have demonstrated decreased expression of sets of may have different effects on the dosage-dependent genes related to synaptic function, including many of the expression of other genes, including those implicated in known ASD risk genes. Surprisingly, despite the 4:1 male ASD-relevant molecular pathways.14,15,16 to female ratio in ASD, these changes in synaptic gene expression were not more evident in males than females. Another remaining challenge is to understand how the However, there was an observed upregulation of genes effects of hundreds of implicated genes converge to cause related to microglial and astrocytic function (brain cells ASD’s common features. And conversely, more work is that provide support for neurons) that was more needed to determine how individual genes and their pronounced in males.13 These gene expression differences interactions with early life events explain the biological may help explain why ASD occurs more frequently in basis of the heterogeneity of ASD symptoms, which range males. Moving forward, new gene expression mapping from severe intellectual disability and absence of verbal technologies have the potential to better characterize language, to mild social deficits with normal cognitive altered patterns of gene expression in specific brain function. With regard to the 4:1 male to female ratio in cell types, offering the opportunity to precisely associate ASD mentioned above, further work is also needed to gene expression differences at a cellular level. In these understand the phenotypic differences between girls and studies, it will be critical to include an examination of boys with ASD, and how these differences should inform gender-related differences in gene expression. development of screening and diagnostic tools, interventions, and services that meet the needs of both girls and boys The impact of sex chromosomes on differences in gene on the autism spectrum. expression between males and females – and how this may contribute to ASD – is also an area of research needing additional attention. The role of genes on the Y (male) and X

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STRUCTURE AND FUNCTION OF BRAIN CIRCUITS IN ASD

STRUCTURE AND FUNCTiON system, a part of the brain which is known to play an important role in learning, memory, and emotions. One of Autism is characterized by atypical patterns in physical the more reproducible findings is a reduction in the number brain connections (structure) and in how regions of Purkinje cells in the . communicate with each other (function). Brain structure in individuals with ASD can be compared to typically Current evidence suggests that early brain overgrowth is developing children using advanced magnetic resonance present in approximately 15% of 2-year-old boys with ASD, imaging (MRI) techniques to measure size and shape but is much less common in girls.24,25 Brain enlargement of brain regions over time, as well as diffusion tensor relative to body size in this subset of boys persists at least imaging (DTI) to examine the structures of the major through 5 years of age26 and is associated with lower connections between brain regions. Brain circuit function language ability at age 3 and reduced intellectual ability at can be investigated using non-invasive markers, such as age 5.27 Currently, the prevailing theory is that early brain functional magnetic resonance imaging (fMRI), overgrowth normalizes during adolescence and adulthood,28 magnetoencephalography (MEG), electroencephalography although this is based on cross-sectional studies. A truly (EEG), and functional near-infrared spectroscopy (fNIRS). longitudinal analysis, where the same individuals are These studies have shown differences in activation patterns imaged throughout life, is needed to clearly establish in individuals with ASD in response to sensory processing this. Studies at the cellular level have begun to describe 17,18,19,20 of visual, tactile, auditory, and verbal stimuli. differences in neuronal growth and organization in ASD brains. Although non-invasive measures of brain connectivity have demonstrated differences between brain regions in Interestingly, recent studies have identified significant persons with ASD compared to controls, it is unclear how inter- and intra-individual variability in neural functioning these differences account for the heterogeneity in ASD in ASD. Heterogeneity in the ASD phenotype also contributes symptoms. Earlier findings from fMRI, DTI, and pathological to greater functional variability within ASD groups. studies highlighted a pattern of reduced long-distance To address this heterogeneity, a greater number of studies 21 connectivity and increased local connectivity. While these are examining dimensional traits in large samples of principles still largely hold, newer research has revealed ASD and groups. greater nuance and specificity.22,23 Ongoing work is linking these functional and structural On the gross anatomical level, the brains of autistic differences to core features of ASD including studies on social individuals appear normal. Microscopic studies have communication, language, and restricted and repetitive reported disordered cell organization with smaller, more behaviors. Recent work has identified neurobiological densely packed neurons in many regions of the limbic correlates of sensory processing in autism,29,30,31 including

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findings of reduced modulation of connectivity between insults, for example those due to infection in utero, premature the thalamus (a brain structure responsible for relaying delivery, or perinatal cerebellar hemorrhage also alter the sensory and motor signals to the as well as construction of brain circuits leading to ASD. regulating consciousness, sleep, and alertness) and cortical regions in response to sound or touch. The extent of this There are continuing challenges in applying animal reduced connectivity was related to parent reports of models to understand the biology of autism. Because, in sensory over-reactivity.30 In the domain of touch, reduced many cases, autism impacts uniquely human aspects of response was seen in ASD children in social-emotional brain social-communicative behavior (e.g., spoken language), regions to a soft caress compared to typically developing developing and measuring analogous phenotypes in children, while increased activation was seen in response animals has proven difficult. Because autism impacts to non-caress-like touch in the brain’s primary sensory brain regions not developed in some animal species, some cortex. This over-activation may be related to the hyper- neural circuitry is not readily amenable to study in these sensitivity to touch seen in some ASD individuals. models. Moving forward, increased use of species more comparable to humans in both biology and behavior will There is a need for a greater understanding of the relationship be necessary. Notably, genetic tools previously limited in between intrinsic functional brain organization during rest application to mice can now be applied in rats and even and functional connectivity dynamics during task states. non-human primates, such as macaques and marmosets. Additionally, there is a need for a better understanding Furthermore, the circuit alterations that have been described of brain function and connectivity during tasks that better in ASD models vary considerably. Variability due to capture the complexity of real-world interactions for methodological differences among labs may diminish the individuals with ASD.32,33 value of the research findings. Incorporation of a more standardized and systematized approach to studying the CiRCUiT ACTiViTY iN ASD altered circuits in ASD models could be valuable to the field.

As is true of almost all brain disorders, the symptoms Fortunately, new powerful technologies for interrogating experienced by individuals with ASD are linked to alterations and modulating brain circuits are revolutionizing in brain circuit function. Alterations in the formation of neuroscience. The BRAIN Initiative is a multi-Federal agency, brain circuits that occur in utero, during infancy, and in public-private partnership in the US to advance brain circuit childhood can have long-lasting impacts on circuit function neurotechnologies and also engage multiple international in adulthood. During these early critical time periods, efforts. These technologies promise to expand the ability connections between brain regions are dramatically molded to understand brain circuit differences due to genetic and by brain activity and may be altered by injury or inflammation. environmental influences that contribute to many diseases, including autism. The brain circuit alterations implicated Identification of genes involved in syndromic autism enable in ASD in animal models can now be explored in detail using the study of the human phenotypes associated with those these new technologies to map neural connections over genetic syndromes as well as phenotypes of genetic animal large expanses of brain,35 record from a large number of models carrying the same mutations. The study of several neurons during a behavioral task, and turn on or off specific forms of syndromic ASD have revealed nervous system types of neurons to understand the nature of brain circuit differences such as differences in abundance of certain cell alterations caused by biological mechanisms tied to ASD. types, in neural circuits, and in brain activity.34 Environmental

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ROLE OF IN BRAIN DEVELOPMENT AND ASD

Increasing evidence suggests immune dysregulation and and synaptic pruning (removing excess or underutilized neuroinflammation may be implicated in the severity and during development).48,49 Analyses of autism pathogenesis of the autism phenotype.36,37,38 One recent brain tissue reveal alterations in genes that control microglial meta-analysis of 17 studies identified significantly altered activation states and an association between microglia concentrations of immune regulators known as cytokines dysregulation and neuronal activity.50 Evidence from human in ASD patients compared to healthy controls, adding to postmortem studies have found increased microglia the evidence of increased inflammatory signals in ASD.39 activation, density, or size in various brain regions.51,52,53 Despite many studies demonstrating altered levels of Animal studies have also shown that microglia-mediated immune biomarkers and abnormal immune function in both synaptic remodeling is abnormal in a mouse model of the peripheral and central nervous system in ASD, it is autism.54 In addition, an increase in activated microglia in not clear whether the immune system plays a direct role the amygdala, which plays a primary role in the processing of in the development of the disorder via an impairment emotional reactions, was observed in a subset of human of neurodevelopmental processes. Several recent studies cases (two out of eight).55 suggest that maternal immunological factors may play a role in the pathogenesis of ASD during prenatal Further investigation of the role of microglia in animal models development.40,41,42,43,44,45,46 of ASD are warranted based on our emerging understanding of their role in normal development and potential contribution Microglia are innate immune cells that reside in the central to ASD phenotypes. In addition, more studies are needed nervous system and are activated in response to infection to identify the roles of molecules secreted by immune cells or inflammation. Even in their so-called resting state, they on brain development and function. perform critical functions, including regulating the number of neural precursor cells,47 maintaining synaptic organization,

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DEVELOPMENT, NATURAL HISTORY, AND VARIABILITY IN ASD

BRAiN DEVELOPMENT, DEVELOPMENTAL before behavioral signs of atypical development emerge. TRAJECTORiES, AND NATURAL HiSTORY Historically, research on early markers has focused on OF ASD infant siblings of children with ASD, not only because they are at heightened risk for ASD and other developmental ASD is a , yet most studies of brain delays (prevalence estimates of ASD up to 20%), but also structure and function have focused on data collected because they are identified prenatally and can be followed from a discrete ASD population at a specific point in time from birth.59,60,61,62,63,64 This body of research has led to or from postmortem brains. More studies are needed the identification of atypical behaviors – particularly in the that will enhance our understanding of brain development, social domain – within the first years of life,65 with some through longitudinal studies that gather imaging data evidence of motor delays66 and altered patterns of social (using methods such as structural and functional MRI attention67 within the first year. and electroencephalography) from the same set of subjects repeatedly over an extended study period. Furthermore, The brain connectivity changes that underlie autism advances in human imaging technology and longitudinal are not static; their manifestations appear during the study designs may provide an opportunity to better dramatically dynamic period of brain development and distinguish true causes from consequences of specific continue to change over the lifespan of the individual. pathological findings by making it possible to image brain Therefore, understanding the biology of autism requires tissue in live subjects throughout the lifespan. These kinds large longitudinal studies to chart the trajectory of neural of studies will require standardized acquisition parameters circuits over time, including how they adapt to inborn wiring to enable comparability across studies, and robust data errors and environmental exposures. Studies are needed sharing policies should be in place to enable expert analysis that include pregnancy and follow maternal exposures and 56,577 of the data by a variety of computational scientists. response, fetal development, and brain response to events that occur in utero and perinatally. Fortunately, new imaging Although defined behaviorally, the identification of causative techniques may enable safe study of the developing brain genetic variants has begun to suggest the neurobiological during prenatal development. The genetic and phenotypic basis of ASD. Many of these variants have been found heterogeneity of ASD are daunting, making generalization to converge on basic processes in early brain development, of findings dependent upon large numbers of subjects. such as cortical organization, formation and function, Furthermore, the measures in these studies are often the balance between neuronal excitation and inhibition, complex and subject to variability in their acquisition or and the development of robust, functional neuronal analysis. This makes them difficult to reproduce and networks that may impact early perceptual and cognitive diminishes their value. To compare among individuals processes.34,58 These processes may be measured through requires standardization; variability needs to be minimized functional and structural neuroimaging methods well and then measured for inclusion in the analysis.

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The Lifespan Connectome Project is one example of structural MRI at ages 6, 12, and 24 months. Differences a sophisticated brain imaging study of a large sample in white matter tract development from 6 to 24 months, of typically developing individuals across the lifespan. particularly a slower change in a measure of fiber density, have been reported in infants who develop ASD.68 More Methods to examine brain development are now more recently, the IBIS Network has identified hyperexpansion powerful, and normative data in typical development are of the cortical surface area between ages 6 and 12 months needed to inform the studies in atypical development. in those infants who developed ASD, with brain volume One such collaborative effort includes the Baby Connectome overgrowth related to autism severity.69 Another recent Project (BCP), which is a longitudinal study intended to study found that infants who went on to develop ASD provide a better understanding of how the brain develops exhibited a significant excess of cerebrospinal fluid from infancy through early childhood and the factors surrounding the brain at 6 to 24 months.70 These studies that contribute to healthy brain development. Variables have shown that brain changes can be observed at as early of interest include patterns of structural and functional as 6 months of life, even in children that show a regressive connectivity and their relationship to core behavioral skills onset of autism at 18-24 months. At the present time, there from infancy to early childhood. Additional biological have been virtually no studies in which high-risk children (e.g., genetic markers) and environmental measures are studied earlier than 6 months, but this is a challenge (e.g., family demographics) are being collected and examined worthy of future research efforts. to provide a more comprehensive picture of the factors that affect brain development. Study data will be made Going forward, large, organized longitudinal studies available to the scientific community as it is measured. across the lifespan are needed to better understand This knowledge will be tremendously useful in understanding developmental trajectories and natural history of ASD. Early brain function and how early interventions may shape our results underscore the need to track and better understand brain throughout our lifespan. Such coordinated efforts, longitudinal changes in brain development before autism with standardization of data acquisition and analysis, are symptoms emerge.68,69 Such measures can help us to needed in other imaging methods, such as EEG or MEG, understand the underlying mechanisms of atypical and in the integration of multiple modes of imaging development and to elucidate the ideal timing and targets (structural and functional), particularly as they relate to for early interventions. These measures can also link back later behavior. Ultimately, these studies will lead to the to genetic mechanisms implicated in neurodevelopmental development of more scalable imaging tools that can be disorders more directly than behavioral assays. However, applied to large, more representative cohorts of infants and new mobile technologies are becoming available to monitor children. Additionally, as ASD manifests during development, and quantify behavior over long time periods which should it will be important to understand the critical windows aid autism research in its integration of behavior with ge- during which circuit abnormalities may be reversible. netics, neuropsychological tests, neuroimaging, and other measures of biological function. The earliest behavioral and Research has suggested the prenatal period and first years of biological markers of risk, the unfolding of ASD in early life are the critical time period for the onset and development infancy, and the comparison of these developmental of autism. Promising results have emerged from the Infant processes in defined genetic syndromes with those found Brain Imaging Study (IBIS), in which low- and high-risk in familial risk groups remain relatively unexplored and (sibling) infants are being examined longitudinally with offer promising avenues for new research. Other key

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questions that can be answered through longitudinal studies of behavioral intervention knowledge that may enable of brain development include how features of ASD change high-quality imaging in ASD children with intellectual over time,71,72 identification of adaptive brain changes in impairment, thus allowing for imaging studies on cohorts response to a developmental disturbance, changes that that are more representative of the heterogeneous may be either beneficial or harmful, adaptive changes in ASD population.77 brain function and structure that predict response to interventions, and developmental changes that inform Characterizing relevant aspects of heterogeneity is core developmental features, such as language or complex. Some factors, such as biological sex and genetic nonverbal cognition. contributions, are developmentally stable and represent viable starting points for constraining and characterizing PHENOTYPES AND SUBTYPES heterogeneity. However, within these categories, there is nested heterogeneity that has not yet been characterized Even within genetically determined syndromic ASD, there in a consistent, reliable, or universal fashion. For example, is considerable variability in the range and severity of distinct biological processes may be associated with symptoms. ASD most likely occurs due to a complex genetic cognition, language, social motivation, repetitive behaviors, architecture composed of multiple interacting biological or other factors that are challenging to quantify and are pathways which combine to cause the phenotypic richness variable across development. Great progress has been that can be observed even between siblings.73 In preliminary made in developing nuanced and reliable measures of these studies that require replication, genetic associations have constructs, and their integration into large studies of been found to segregate to some extent with specific biology is necessary to elucidate distinct contributors to phenotypes such as ASD with and without intellectual varying manifestations of autism. A notable challenge impairment,3 ASD with motor speech disorder, 74,75 and to autism research is the poor understanding of many of other subphenotypes.76,7 Certain functional and structural these factors in typical development; rigorous and changes in brain circuits are associated with specific longitudinal approaches to characterization and biological phenotypes. The basic biology of circuits underlying measurement in control samples are essential aggression, anxiety, theory of mind (ability to understand steps to developing a meaningful frame of reference and reason about the thoughts of others), language for understanding atypical development in autism. development, attention, and social cognition is still not completely understood, but fundamental advances would A broad challenge to clinical studies is heterogeneity in enable the search for disturbances in persons with ASD to the diagnostic entity of autism itself. Rather than a singular eventually understand phenotypic variability. To accomplish diagnostic construct, autism represents a common this, it is necessary to standardize the classification criteria behaviorally defined developmental pathway reflecting and include greater sample size in linking phenotypes to numerous etiologies and an unknown number of involved , brain imaging, and brain tissue examination. In mechanisms. Previous studies with small sample addition, MRI studies have traditionally been difficult in ASD sizes provide limited information and make it difficult individuals with intellectual impairment because of the to differentiate between what is true heterogeneity in the requirement to remain still and understand directions in disease mechanism and what is simply variability due to the MRI scanner; more of these studies have been done on underpowered statistics, inconsistent approaches, and high-functioning individuals. However, new methodologies diverse methodologies for measuring biological processes. have been developed that capitalize on the large body

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It will be important to conduct large studies involving BiOMARKERS AND PREDiCTiON OF ASD thousands of individuals with autism with structured The past few years have seen an increase in large-scale and and consistent measurement according to rigorous longitudinal datasets. This, combined with increasingly methodological standards. For example, the Autism sophisticated analytical techniques, has allowed for a more Biomarkers Consortium for Clinical Trials (ABC-CT) refined search for potential biomarkers of ASD. Pre-diagnosis project is focused on developing biomarkers for ASD fMRI response to speech combined with clinical behavioral subgroups based on evaluations of brain function, visual measures in toddlers and young children predicted ASD attention, as well as behavior and speech in children aged prognosis.78 Brain response to social stimuli (biological 6-11. Such studies will enable investigators to determine motion) accurately predicts whether boys have autism, the presence of mechanistically meaningful subgroups and, but not girls79 – again highlighting the need for a greater in the absence of true subgroups, to understand continuous understanding of the neurobiology of females with ASD. relationships among biological processes and quantifiable Potential biomarkers are also being developed to aspects of the phenotype. It is critical that studies are predict treatment outcome success.80,81 There have also designed with longitudinal components that can offer been advances in the identification of biomarkers that can insight into changes associated with human development predict autism risk in infants. Utilizing an infant sibling across the lifespan. The National Database for Autism design, two promising biomarkers have been identified in Research (NDAR) provides a medium for making datasets infants as young as 6 months of age, including surface area publicly available to benefit from the universe of analytic expansion in specific cortical regions from 6-12 months resources beyond those maintained at individual of age69 and the presence of excess cerebrospinal fluid laboratories carrying out the research. surrounding the brain at 6-24 months.70,82 Ongoing work is using data-driven classification and prediction methods, which if combined with validation and replication efforts should further refine and develop these biomarkers.

CO-OCCURRING CONDITIONS IN ASD

ASD is associated with a wide range of co-occurring Additionally, more research is needed to investigate the conditions that can cause an increased financial potential role of these conditions in the underlying causes and psychological burden on families and caregivers of ASD. as well as decreased quality of life for persons with ASD. Since 2013, much progress has been made in understanding GASTROiNTESTiNAL CONDiTiONS the prevalence and underlying biology of conditions that GI symptoms and an inflammatory mucosal pathology commonly co-occur with ASD, including gastrointestinal have been demonstrated in several studies of ASD, and it has (GI) disturbances, , sleep disorders, psychiatric been estimated that up to 50% of ASD patients have feeding disorders, and immune/metabolic co-occurring conditions. and GI conditions.83,84,85,86 A recent rigorous meta-analysis

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of 15 studies in 2,215 children with ASD indicated a that early life seizures may result in altered function of greater than two-fold elevated risk of GI symptoms among systems and intrinsic neuronal children with ASD than in those without ASD, and that properties during neurodevelopment that lead to the children with ASD are more prone to specific symptoms of disrupted cortical connectivity that is characteristic of ASD.98 abdominal pain, constipation, and diarrhea.87 Importantly, The PREVeNT trial (Preventing Epilepsy Using Vigabatrin many of the genes implicated in autism are also expressed in Infants with Tuberous Sclerosis Complex) is an in the neurons outside of the central nervous system, NIH-funded Phase II clinical trial that began in 2017 and including those that innervate the GI system. However, will assess whether anti-epileptic treatment can prevent relatively little is known about autism risk gene functions development of epilepsy in infants with TSC who display in the digestive tract, as well as in sensory perception EEG biomarkers of abnormal brain activity prior to and motor function.88 Genetic changes implicated in ASD onset of seizures (NCT02849457). may impact function of both the brain and GI system. SLEEP AND SENSORY DiSORDERS Additionally, alterations in the composition of the gut ASD is frequently accompanied by a variety of sleep microbiome have been implicated as playing a causal role problems that worsen daytime behaviors and core symptoms in ASD pathophysiology. Studies of fecal DNA have found such as stereotypic, self-injurious, and repetitive behaviors. certain bacterial clusters are overrepresented in children with Studies indicate the prevalence of sleep problems in ASD ASD and GI complaints compared to neurotypical children are as high as 50-80% and that children with ASD have with similar GI complaints, and demonstrate an altered higher prevalence of sleep disorders than children with microbial community with respect to both bacteria and fungi other neurodevelopmental disorders.99 The most common in ASD.89,90,91 Current research suggests that disturbances sleep problems reported in ASD are sleep-onset insomnia, within the microbiota-gut-brain axis may contribute to or difficulty initiating sleep, and sleep-maintenance insomnia, the occurrence and development of ASD and that the or decreased sleep duration. Several , application of modulators such as probiotics, helminths, including serotonin, , and gamma-aminobutyric and certain special diets may prove useful for the acid (GABA) play a vital role in the maintenance of treatment of ASD.92 sleep-wake cycles, and abnormal levels of these 100 EPiLEPSY neurotransmitters have been described in ASD.

Studies have shown that many of the risk genes for epilepsy Hyper- and hypo-sensory abnormalities are frequently and autism overlap.93 Several studies demonstrate an observed in individuals with autism and may have negative increased prevalence of epilepsy in individuals with ASD, impacts on cognitive performance, social interactions, well above the general population risk, and some suggest and stress. Recent work in animal models suggests that that there is an increased risk of epilepsy in females peripheral disorders have widespread impact on behavior with ASD when compared to males with ASD.94,95,96 in experimental animals.88 A question for future research The largest study to date comparing the autism phenotype is whether hard-wired abnormalities that disturb sensory in children with ASD with and without epilepsy found that processing secondarily contribute to alterations in brain children with ASD and epilepsy had significantly more circuits involved in behavioral and social functions. autism symptoms and maladaptive behaviors than children This may lead to novel ways to therapeutically alter the without epilepsy.97 Research in animal models suggests developing child’s sensory environment in order to

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improve later-developing social skills. Further, it will be frequent co-occurring conditions were depression and important to explore whether and how impairments in , and that obsessive-compulsive disorder sensory processing during infancy may alter early brain and alcohol abuse/dependence were also observed.102 development and contribute to the development of Recent studies reveal that consistently high levels of social and cognitive impairments later in life. psychological symptoms and distress occur across the adult lifespan in ASD, where individuals with more severe PSYCHiATRiC DiSORDERS depression and anxiety disorders demonstrated more severe ASD symptoms.103,104 At the molecular level, one study It has been estimated that 69% of patients with ASD suffer suggests that a variation in the serotonin 2A receptor gene from co-occurring psychiatric disorders and symptoms.101 may modulate the severity of depression symptoms in As with the general population, age appears to be a relevant children with ASD.105 factor for psychopathology in patients with ASD. One study of adults with Asperger’s Syndrome showed that the most

RESEARCH POLICY ISSUES

A major challenge for the biological sciences is to utilize Larger longitudinal studies require coordination among the most sophisticated technologies that produce ever- research centers and a shift in focus toward team science enlarging data sets while still ensuring the rigor and quality across multiple disciplines. The coordinated collection and of research.106 Moving forward, the field should embrace analysis of valuable imaging, behavioral, genetic, pheno- policies that enhance the replicability of findings and promote typic, and iPSC data can be enhanced by the recruitment transparent reporting of experimental methods, use of of a more diverse workforce that includes not only common data elements, and sharing of data and analysis neuroscientists, immunologists, and psychiatrists, but also tools. Follow-up validation studies are a necessary part of experts in bioinformatics, machine learning, and behavior this process, and data sharing should be integrated into monitoring device engineers. the design of studies from the beginning. The National Institute of Mental Health NDAR platform is a valuable The inclusion of persons on the autism spectrum in research repository for high-quality ASD data, tools, and plans and messaging is crucial to identifying practical methodologies that researchers should leverage to applications for improving the quality of life for ASD patients enable re-analysis of data and facilitate collaboration and their families. Standard methods for behavioral to accelerate research progress. measurements and tracking quality of life across the lifespan are essential for addressing prescient issues supporting individuals with ASD in their daily lives.

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SUMMARY

Significant progress in understanding the biological basis of autism has been made, but considerable challenges remain. Though there is a desire to demonstrate the impact of treatment on brain function, fundamental research that will allow us to fully understand the importance of alterations in brain function on development is needed. Basic science on the underlying biology of ASD continues to be critical to provide the foundation for translational advances that will lead to effective treatments.

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OBJECTIVES

OBJECTiVE 1: Foster research to better understand the processes of early development, molecular and neurodevelopmental mechanisms, and brain circuitry that contribute to the structural and functional basis of ASD.

Examples:

• Identify neural circuit abnormalities that occur in significant groups of ASD individuals.

• Understand the role of the immune system and metabolic processes in ASD, including aspects such as the fever effect (behavioral improvement coincident with fever).

• Identify quantitative and reproducible biomarkers or behavioral monitors for ASD of utility in assessing effectiveness of future therapeutic or behavioral intervention trials.

OBJECTiVE 2: Support research to understand the underlying biology of co-occurring conditions in ASD and to understand the relationship of these conditions to ASD.

Examples:

• Determine the molecular basis of epilepsy in ASD.

• Determine the impact of GI dysfunction on ASD related behaviors and cognitive performance.

• Determine the impact of sleep disorders on ASD related behaviors and cognitive performance.

• Determine the relationship of co-occurring psychiatric disorders to ASD and their impact on the health and well-being of people with ASD.

OBJECTiVE 3: Support large-scale longitudinal studies that can answer questions about the development of ASD from pregnancy through adulthood and the natural history of ASD across the lifespan.

Example:

• Support the creation of large cohorts, characterized both phenotypically and genetically through the collection of autism-relevant exposure data and medical data on the parents and child from the prenatal period to adulthood.

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27 QUESTION WHAT CAUSES ASD, AND CAN DISABLING ASPECTS OF ASD BE 3 PREVENTED OR PREEMPTED? 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Aspirational Goal: Causes of ASD will be discovered that inform diagnosis, prognosis, and interventions and lead to prevention or preemption of the challenges and disabilities of ASD.

INTRODUCTION

Since the last Strategic Plan update published in 2013, and a particular life history of environmental there have been substantial advances in the understanding exposure (the exposome). of factors that contribute to a diagnosis of autism spectrum disorder. Few would dispute that the causes of ASD are The title of this chapter, which has been modified from many and include both genetic and environmental the 2013 Strategic Plan Update, emphasizes the desire to factors. There has been an increased appreciation in the understand the causes of the disabling aspects of autism last five years of the incredible complexity and interplay spectrum disorder. These go beyond the core symptoms of these factors in the development of autism. Indeed, of deficits in social communication and the occurrence modifications in more than 100 genes are now known to of restricted patterns of behavior or interests to include increase the probability of an autism diagnosis1,2 and very what are typically referred to as co-occurring symptoms. reasonable predictions are that 1,000 or more autism risk In many cases, progress on the causes of these co-occurring genes may ultimately be identified.1 A plethora of potential symptoms is ahead of that for the core symptoms environmental challenges have also been associated with of autism. There is a growing appreciation that the causes autism, although studies in this area have not undergone of these medical problems urgently need to be addressed. the same exponential progress as genomics research. They may be due to biological factors that are also causal There has also been increasing emphasis on events during of autism, manifestations of autistic behavioral problems pregnancy, such as influenza infection, as potential causes such as poor diet that may lead to medical issues, or of neurodevelopmental disorders. But, these studies have medical access issues which lead to poorer medical care. raised the interesting issue that environmental risks affect Regardless of the causes, this is a clear gap in autism different people differently. This is the so-called “genes by research and intervention and urgently needs additional environment” interaction. More and more modern medical research attention and efforts at resolution. problems are linked to the combination of a particular

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The title to this chapter has changed (from “What caused on efforts at prevention. In the hypothetical situation that this to happen and can it be prevented?”) because the a known cause of autism is identified, the question arises movement has had a great impact on the whether the cause should be eliminated thus preventing IACC and on the premises of the Strategic Plan enterprise. some cases of autism. If the discussion were related to It is fully appreciated now that some features of autism , the answer would be clear. But, in autism it is not. should not necessarily be targets for prevention. As discussed There is clearly an increased sensitivity to any procedure above, it is the most disabling features of autism that or practice that would be directed at preventing the are now the major targets of prevention or preemption. totality of autism, and this is reflected in the emphasis Discussions of the causes of ASD always ultimately touch of this chapter.

GENETIC RISK FACTORS

The application of genomic studies has significantly advanced estimated 8% of autism diagnoses.15 Recent whole genome the understanding of genetic risk factors for ASD. Dozens sequencing studies of a large diverse ASD collection revealed of new ASD susceptibility genes have been identified over a molecular basis in 11.2% of participants, including the the past 5 years and genome-wide technologies have finding that 7.2% carried copy number variations (CNVs; facilitated a molecular diagnosis in ~5-40% of ASD cases. repeated sequences in the genome that vary between This range in the rate of detection depends on the group individuals) or chromosomal abnormalities,16 which further of subjects examined and the technology used. Studies emphasize the need to use comprehensive genomic comparing individuals with ASD to typically developing technologies.17 Overall, a consistent observation emerging individuals have indicated that as much as 7-8% of people from genomic studies is the vast genetic heterogeneity with ASD carry either a large pathological DNA involved in ASD.18,19,20 or duplication.3,4,5,6 Earlier results from DNA sequencing studies have further confirmed the role of gene-disruptive Follow-up evaluation of individuals with ASD who have mutations in ASD,7,8,9,10 and more recent data also disruptive mutations to the same gene or genomic region support and add to these findings.11,12,13 The rates of de novo has further illuminated features and patterns of behaviors (new, spontaneous, non-inherited) likely gene-disruptive (sub-phenotypes) linked to these genetically defined (LGD) and missense mutations (which result in amino subgroups. Clinical characterization of cohorts with acid changes) are significantly higher in individuals with disruptive gene mutations has revealed real, but subtle, ASD compared to their unaffected siblings (while the rate phenotypic patterns tied to particular genes. Patterns of of mutations which do not alter amino acid sequence or behavior linked to sub-phenotypes can prove helpful for biology does not differ).12 As much as 21% of autism establishing guidelines of care for clinicians. While major diagnoses may be accounted for by de novo single-nucleotide advances have been made through the application of genomic variant (SNV) and insertion/deletion mutations.14 technologies, gaps exist in our understanding of the Additionally, inherited LGD mutations have been found contribution of regulatory and other genomic regions to ASD to show a preferential transmission from mothers to sons, risk. Whole genome sequencing will begin to illuminate indicating another potential risk factor contributing to an the role of non-gene coding regions of the genome.

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HERiTABiLiTY variation, de novo variation, , and inherited rare variation.11,12,15,19,30,31,32,33 Common polygenic ASD is highly familial, so that siblings of children with autism variation may account for the greatest fraction of genetic are 10-20 times more likely to receive an ASD diagnosis influence, and approximately 20-50% of population liability. themselves than non-siblings.21,22,23 studies beginning De novo variation accounts for less liability at a population in 197724 have provided significant evidence that ASD is level, but can have a very strong impact on the individuals strongly associated with genetic factors. All 13 twin studies who carry such variants.12,32 These data represent population on autism to date have found genetic and environmental risk; a crucial next step is integrating our understanding contributions to autism, although the proportions of the of rare variants of large effect with more common two factors and interpretations have varied substantially. polygenic risk factors to more accurately predict ASD One research team,25 for example, concluded that over on an individual level. 50% of the risk for autism in identical could be explained by shared environmental factors, whereas SEx DiFFERENCES genetic accounted for 37%. This somewhat surprising finding—that environmental factors contribute The overrepresentation of males among those diagnosed 34,35,36 more substantially than genetics—has been challenged with ASD has been observed for decades. Overall, the by a more recent, large-scale ,26 which found male to female (m:f) ratio is approximately 4:1, but that that the largest contribution to autism liability comes from ratio varies substantially based on IQ and other features 34,37,38 additive genetic effects. A recent meta-analysis concludes of ascertainment. Specifically, in individuals with that the are due to strong genetic effects, ASD and very low IQ, the male:female ratio is commonly and that shared environmental influences are seen only if estimated at 2:1 or 3:1; in individuals with ASD and high IQ, the most severe forms of autism are included.27 A recent the m:f ratio becomes very large, often 7:1 or greater. This survey of autism twin studies finds that concordance pattern has been consistently observed during the period for monozygotic twins is roughly 45%, versus 16% for of otherwise rapid changes in the epidemiology of ASD. dizygotic twins.28 Thus, twin and family data suggest that There are several theories as to why males and females between people accounts for a very might differ in their observed ASD liability.36 Among substantial portion of the liability to ASD at a population biological theories, the extreme male brain hypothesis posits level. But, if autism had a completely genetic etiology, we that the male brain is predisposed to many features that would expect a much higher concordance (or shared ASD) are on the ASD spectrum.39,40 The ‘female protective effect’ rate in monozygotic twins; the lower rate may reflect, in part, (FPE) hypothesis in ASD is amongst the most commonly that even monozygotic twins do not share an identical investigated in recent genomics studies.41 The FPE hypothesis environment prenatally. suggests that females are ‘protected’ from ASD GENOMiC ARCHiTECTURE (for unspecified reasons) such that, on average, a greater number of risk factors (or genetic “hits”) is necessary for The recent successes in ASD genetic studies have confirmed a girl to gain a diagnosis of ASD. In the context of de novo the importance of genetic risk factors. Similar to other and gene-disruptive inherited variation, that suggestion has common psychiatric disorders, the genomic architecture been supported by the recent genetics literature.6,12,15,42 of ASD is complex, involving both common and rare forms of Deleterious CNVs are three times more likely to be 29 genetic variation, including common polygenic (multi-gene) identified in autistic females when compared to males,42

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and loss-of-function mutations show a maternal transmission children with ASD.54,55 Some of the ASD-associated de novo disequilibrium suggesting mothers are more likely to be events that result in problems in production are carriers of such mutations than fathers.15 Similarly, classes more likely to be seen in cases of intellectual disability than of de novo variation that are strongly associated with ASD in ASD itself.56 Similarly, several CNVs that increase risk risk are approximately twice as likely to be observed in for also increase risk for ASD.57,58,59,60,61 female cases, as compared to male cases. Recent gene This is consistent with these mutations having major expression analysis demonstrates that autism risk genes, effects on brain development, which subsequently can rather than being sexually dimorphic themselves, interact manifest as different clinical outcomes. However, there with pathways and cell types that themselves are are many intellectual disability genes that do not appear sexually dimorphic.43 to increase risk for ASD.62 So, understanding why some large-effect mutations that cause intellectual disability OVERLAP WiTH OTHER DiSORDERS substantially increase risk for ASD, while others may not, remains an area of future investigation.63 Neuropsychiatric and developmental disorders share many genetic risk factors, and this varies depending on the specific GENETiC TESTiNG AND COMMUNiCATiON disorders being compared.30,44,45 ASD shares common OF RiSK risk genes with other neuropsychiatric disorders such as schizophrenia,46,47 and autism is sometimes a feature of Genetic testing is recommended by the Accreditation Council other neurodevelopmental syndromes such as Fragile X for Graduate Medical Education for those at increased risk syndrome, Rett syndrome, tuberous sclerosis, and Phelan for ASD.64,65 This includes chromosomal microarray (CMA) McDermid syndrome.48,49,50,51 The common, polygenic followed by Fragile X testing and other specific tests influences on ASD risk are similarly associated with multiple depending on the symptoms that are observed. Several phenotypic outcomes (different combinations of risk genes studies review the current recommendations for genetic can lead to different neuropsychiatric and developmental testing in ASD.55 In addition to its usage in research studies, conditions). In recent studies, and in contrast to the de whole exome sequencing (WES) has been shown to have novo findings, common polygenic risk for ASD has been a high yield in clinical populations with developmental positively associated with general cognitive ability, logical disorders including ASD. Thus, we expect that WES will memory, and verbal intelligence.52 On average, ASD shares gradually supplant CMA.66,67 most risk with schizophrenia in the population, followed by bipolar disorder, but very little with substance abuse Given the incomplete of many large effect or major depression. It does not appear that this overlap or familial genetic risk factors, care must be taken in involves the majority of common genetic risk for each pre-symptomatic or prospective risk counseling. Further disorder, and the extent to which overlap occurs, and what understanding of the causal relationship between identified biological factors it represents, remain under investigation. ASD risk genes and clinical outcomes is needed before guidelines for genetic counseling can be illuminated. Rare familial mutations that cause syndromic ASD and Understanding parental concerns and attitudes when de novo (spontaneous) genetic influences on ASD risk are communicating complex genetic information that has also strongly associated with intellectual disability, an impact on family planning is also important.68,69 epilepsy, and global developmental delay;12,53 neurological co-occurring conditions are identified in the majority of

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NEW LARGE-SCALE GENETiCS STUDiES LAUNCHED iN THE LAST 5 YEARS

Studies of the genetic architecture of ASD have resulted in the appreciation that much larger groups of subjects are needed to fully understand its complexity. In the last 5 years, several large-scale projects have been initiated. Recent large-scale efforts include MSSNG (funded by ), which seeks to sequence the of 10,000 individuals affected by ASD, and the SPARK study (funded by the Simons Foundation), which seeks to sequence exomes of 50,000 families affected by autism. These studies are expected to not only identify additional autism risk genes but to also contribute to an understanding of the common variant patterns that enable expression of the mutations.

POLiCY iMPLiCATiONS OF ADVANCES iN GENOMiC SCiENCE

New technology and testing can also lead to increases in healthcare disparities; we must be vigilant to avoid this and support policies that enable access to all. Because of differences in population histories, understanding of genetic risk in one population may not be informative in others. This imparts an imperative to study diverse populations. Further, given the role of rare variants that will have very distinct frequencies in different populations, having information from diverse populations will be critical for the interpretation of genetic studies. When predictive testing is performed, care must be taken to ensure accurate prospective/predictive testing and that information about accurate probabilities of particular outcomes are communicated effectively and not mistakenly understood as absolutes. This requires genetic counselors or other professionals trained specifically in the communication of genetic risk to patients. This will be an increasingly important manpower issue as genetic information expands over the next decade.

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ENVIRONMENTAL RISK FACTORS, INDIVIDUALLY AND IN COMBINATIONS OVER TIME

The growing number of studies that are exploring SUSCEPTiBLE PERiODS DURiNG environmental risk factors reflect an emerging consensus DEVELOPMENT that non-genetic avenues of research are also likely to The concept of windows of susceptibility, a central principle bear fruit. In this Strategic Plan, it is advantageous for in environmental health sciences, is relevant to studies the IACC to adopt a broad definition of studies on of environmental risks in ASD. Many lines of evidence “environment” as encompassing research on all potentially point to prenatal origins of ASD.70,71,72,73,74,75 In addition, non-heritable etiologic influences. This includes studies very large epidemiological studies link maternal bacterial of exogenous exposures such as pesticides, endocrine or viral infection during specific times of pregnancy to disrupting and other industrial chemicals, pharmaceuticals, increased risk for ASD in the offspring.76 heavy metals, infectious agents, dietary factors, as well as other factors, such as parental age, maternal medical The periods of prenatal development that are most relevant conditions, birth complications, and time between to environmental risks for ASD are incompletely understood, pregnancies. Some of these “environmental” factors however, and may be dosage- and/or exposure-dependent.77 might themselves be genetically influenced, while others When considered together, many existing ASD studies might be mediating the effects of exogenous exposure. suggest that preconception and early gestation are PREVENTiON OR AMELiORATiON OF vulnerable periods for environmental exposures. This has DiSABLiNG ASPECTS OF ASD been supported by previous reports linking autism symptoms to maternal ingestion of drugs such as thalidomide78,79 Research on environmental contributors to ASD should and valproic acid.79,80 Other factors associated with ASD routinely collect and make use of data on specific ASD risk include preterm birth,81,82,83,84 advanced maternal and symptoms, the levels of symptoms and impairment, as well paternal age at conception85,86,87,88 and short inter-pregnancy as co-occurring conditions. As linkages between exposures interval.89,90 In addition, the preconception/periconception and specific impairing aspects of ASD are revealed, public period may be critical for the observed association of health strategies can be tailored to prevent or mitigate decreased ASD risk with maternal folate intake.91,92 these features by reducing harmful exposures and/or increasing factors that confer protection or resilience. A few of the studies on air pollution exposure Additionally, improved understanding of what role suggest an enhanced risk in the later part of pregnancy.93,94 environmental factors play in ASD severity (including Evidence from the broader neurotoxicology literature95 risk for co-occurring conditions) might eventually inform also indicates that exposures in the late prenatal and early strategies for identifying children in need of specific postnatal periods can exert significant effects on a wide types of early intervention services. range of brain and behavior phenotypes during the first years of life. All of these time windows cover critical stages

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of rapid brain development and are also characterized are represented in ASD research and that disparities in by immaturity of both the immune system and metabolic environmental risk factor exposure are addressed. detoxification mechanisms. These features combine to Inclusion of these vulnerable population subgroups in ASD offer vulnerability and provide biological plausibility for studies may, in some regions, be particularly challenging environmental impact on ASD risk extending from when studies recruit from young children with a past preconception into the early postnatal period. Additional ASD diagnosis. Data from the Autism and Developmental attention to the timing of exposures relative to the cascade Disabilities Monitoring (ADDM) Network indicate that of events that unfold during brain development is needed non-Hispanic black (NHB) children are significantly less to identify and understand the molecular basis of likely than non-Hispanic white (NHW) children to receive exposure-associated ASD risk. With this in mind, study an early comprehensive developmental evaluation,100 and designs and biomarkers of exposure should be chosen Hispanic children are less likely to receive an ASD to capture prenatal and early life exposures. identification by age 8 in comparison to NHW and NHB children. These findings underscore the need to carefully STUDiES iN LARGE AND DiVERSE consider case ascertainment strategies that do not rely POPULATiONS solely on previous ASD diagnosis in designing studies of ASD risk factors. While the number of ASD epidemiology studies and the resulting data are growing through efforts such as the Given the clear differential in ASD risk in males and females, Early Autism Risk Longitudinal Investigation (EARLI) and studies which examine risk and protective factors within Markers of Autism Risk in Babies-Learning Early Signs sex-specific subgroups are especially important. However, (MARBLES), most potential environmental risk factors given the lower ASD prevalence in females, nearly all studies have not been investigated sufficiently to draw firm to date have not had a sufficient sample of females to conclusions.96 The limitations inherent to observational conduct such analyses. Thus, additional efforts are needed studies mean that multiple studies in different populations to increase representation of females in ASD studies to and settings, with high-quality measures of exposure enable meaningful analyses of sex-specific differences and adequate controls, are needed to reconcile disparate and the role of both genetic and environmental factors in findings and establish robust linkages of an environmental affecting those differences. The Environmental Influences exposure to ASD risk. The likelihood that many different on Children’s Health Outcomes (ECHO) initiative of the factors, each with modest effect, will contribute to ASD National Institutes of Health is combining data from more means that large sample sizes may be needed to detect than 78 cohorts comprising approximately 50,000 children associations with exposure, especially for those and 40,000 women. Although the extent of ASD-related exposures with low prevalence. measures that are, or will be, included in ECHO has not yet been established, this initiative represents an exceptional Under-represented minority communities and low-income opportunity to study ASD-related traits in large and communities often face disproportionate exposure to diverse populations. harmful environmental chemicals;97,98,99 additional attention is needed to ensure that these populations

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ExPOSURE SCiENCE tools to help characterize the exposome. For example, use of personal sensors and mobile devices can be harnessed One of the most significant obstacles facing to capture many aspects of the exposome in real time. epidemiologic studies of environmental risks for ASD Refinement of more targeted, conventional exposure is exposure assessment. In many studies, exposure assessment tools also has a place in characterizing measures are not readily available for very early the exposome. developmental periods and rely on indirect methods (e.g., participant recall of prior exposures), or utilize General “omics” approaches such as transcriptomics, one or two biologic measurements of compounds with proteomics, metabolomics, and epigenomics show very short half-lives. Direct exposure assessment, promise in identifying molecular response profiles that such as through personal monitoring or use of an adequate can be linked to exposures,105,106,107 and in some cases, time-course of exposure biomarkers, is expensive these profiles persist over time. These downstream and burdensome for participants. Consequently, biomarkers may suggest groupings of exposures that deep characterization of exposure during etiologically operate by similar pathways. Linking direct measures of relevant time periods is typically limited to studies with either individual or classes of exposures or the broad small numbers of participants, yielding low power. exposome with early “omic” markers of biological response in both targeted and non-targeted data analyses can The recent development and application of the concept provide complementary information of potential of the “exposome”101,102 represents a key advance that etiologic relevance. could accelerate progress in identifying environmental risks for ASD. The concept of the exposome calls attention to Because exposomic approaches have the potential to 103,104 the totality of exposures across an individual’s lifespan. generate high-dimensional exposure data, discovery-based In addition to the universe of external environmental analytic methods analogous to those being used in factors, the exposome concept can be extended to include genomics can potentially be applied to uncover novel endogenous biomarkers of exposure response – internal environmental risk factors – ones that would be missed exposures that originate from metabolism and other cellular by approaches that focus on a small number of established processes – as well as more general external factors that or suspected neurotoxicants. An exposomic approach also constitute social determinants of health. Measuring the is well-suited to the simultaneous consideration of multiple exposome comes with challenges in capturing and exposures and risk factors; although, as the genomics field integrating many individual measures over time. Recognizing has learned, very large samples are needed to achieve that no single approach or tool likely will suffice, the field significance in these kinds of analyses. is embracing a multifaceted strategy, using multiple

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LINKAGES BETWEEN GENES AND ENVIRONMENT

GENE AND ENViRONMENTAL STUDiES Availability of low-burden exposure measures that can be incorporated in large-scale genetic studies, perhaps Despite general agreement that both environment and leveraging innovations in exposomics or epigenomics, is genetics contribute to ASD risk, only modest progress has a high priority. Once these data exist in concert in large been made in identifying gene-environment interactions. sample sets, new statistical and analytic approaches for A few epidemiology studies, such as the Childhood gene-environment discovery in human population research Autism Risk from Genes and Environment (CHARGE) can be applied.112 Polygenic risk scores have seen increasing study, have reported an interaction of exposures with use in complex disease studies and can yield improved common or rare structural genetic variation.92,108,109,110,111 efficiency for detecting interaction of genetic risk with However, each study focused on different combinations candidate environmental exposures. The construction of of exposures and genes, they lack independent replication, a “polyenvironment” score, analogous to a polygenic risk and two of these studies addressed severity of symptoms score, could be explored to summarize information from rather than impacts on incidence.108,111 Many large ASD several exposures thought to be acting through common genetic collections have been assembled but most include mechanisms for use in genetic/genomic studies. Other minimal or no exposure information. On the other hand, approaches might include measures of genomic instability studies focused on environmental risks often feature deep such as global copy number burden, used in two different exposure assessment and have incorporated some genetic gene-environment interaction studies.111,113 information, but smaller sample sizes constrain the power of gene-environment interaction analyses. MECHANiSMS OF ENViRONMENTAL RiSK AND GENE-ENViRONMENT iNTERACTiON A major gap has been identified and a concerted effort is needed to enrich existing, ongoing ASD studies by adding Increasing knowledge of genetics has led scientists to genetic data collection to environmental studies and understand gene pathways that affect neural circuits exposure measures to genetic studies. Identifying and rather than single genes acting in isolation. Early studies accounting for genetically driven effects on exposure levels have demonstrated the convergence of genetic influences is critical for interpretation of ASD-exposure associations. and environmental factors in the activity of these different In the autism literature, it is notable that the genes gene pathways,114 providing evidence that genes and implicated in the folic acid association with decreased the environment might work synergistically, rather than ASD risk have not emerged in any of the genetic studies additively. Studies that move beyond identification of using genome-wide screening. Only in mothers who had genetic and environmental risk factors to reveal functional low folic acid intake do those one-carbon metabolizing biological consequences associated with these risk factors genes appear to play an etiologic role.109 At this stage, it are a priority. Epigenomics, metabolomics, transcriptomics, appears that the presence of a ‘main effect’ (a risk factor and proteomics can provide useful functional readouts not dependent on another factor) is not always detectable for this purpose. and that investigation of interacting factors should not require that a main effect of a specific environmental factor or gene/SNP be known. 37 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Model systems provide an attractive means for supporting A significant body of work demonstrates that environmental causality and understanding biological mechanisms that chemicals can alter DNA methylation, and these alterations underlie associations observed in human studies. Human have been linked to changes in gene expression and a induced pluripotent stem cells (hiPSCs) generated from range of behavioral phenotypes.124,125,126 ASD studies that individuals affected by ASD with a known genetic background integrate methylation, exposure, and phenotype data in are being used increasingly to study ASD.115 These provide the same population are a priority. Research to establish a unique opportunity to assess susceptibility of early whether epigenetic marks measured in peripheral tissues developmental processes to environmental chemicals in the are predictive of changes in target tissues is especially context of defined genetic risk.116 There are a few reports important for interpretation of human studies.127 Also needed of screening or computational approaches used to identify are studies that identify exposure-induced impacts on a possible environmental exposures that could be priorities full range of epigenomic mechanisms and that determine for pursuit in human studies.114,117 The Collaborative Cross their relevance to ASD. Finally, research to understand and Diversity Outbred mouse populations118 represent how exposure-induced epigenomic changes may transmit important mouse resources that could be harnessed to autism risk across generations is warranted. dissect the contribution of environment to complex disorders such as ASD. Additional efforts that bring MULTiVARiATE RiSK ACROSS COMPLEx together interdisciplinary teams to facilitate integrative SYSTEMS analyses and bidirectional flow of clues from human There is a need to capitalize on findings emerging from observational studies to laboratory-based experiments existing studies to examine how genetic and environmental in model systems are warranted. factors interact to contribute to phenotype, not only at the molecular and cellular level, but also in the broader In addition to the utility of epigenomics (the study of physiological context. For example, a substantial body of the complete set of epigenetic modifications – such as work implicates immune dysregulation in ASD, including methylation – on the genetic material of a cell) as easily the association of ASD with maternal infections and attainable exposure biomarkers, many researchers autoantibodies, cytokine and other immune biomarker recognize the potential for mechanistic roles in ASD. signatures, functional alterations in immune cell subsets,128 Epigenomics is a leading candidate for mediating effects and differential expression of innate immune and of exposures on regulation of transcription (the first step inflammatory genes.129 These findings together have in gene expression)119,120,121 and could provide a point of motivated studies exploring how a range of environmental convergence for genes and environment in autism risk. exposures may contribute to the immune alterations observed Multiple lines of evidence implicate altered epigenetic in ASD, some of which have been detectable at birth.130 marks in ASD etiology. Several known genetic disorders with ASD-related presentation, such as Fragile X and The endocrine system is another promising area of , have established epigenetic inquiry. The established role of hormonal systems in brain mechanisms. Further, results from rare-variant ASD genetic development, the marked male bias in ASD, and a growing discoveries point to remodeling of genetic material as recognition that many environmental chemicals act as a shared pathway in ASD genetic risk. Few studies have endocrine disrupting chemicals (EDCs) sets the stage directly examined chromatin marks or DNA methylation for investigations exploring possible links between ASD for association with ASD, but some small studies have and EDCs.131 Some research studies have suggested that observed associations.105,122,123

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factors that protect females from autism risk may be found activation and environmental chemicals,135,136 particularly on hormone-sensitive genes,132 and these could be targets during early life when the microbiome is being colonized. for EDCs. Further work elucidating connections across A role for the microbiome in metabolism of environmental metabolic, hormonal, and central nervous systems in the chemicals is now established.137,138 This means that context of EDCs is needed. differences among individuals in microbiome composition can affect the internal dose and biotransformation of The microbiome (the combined genetic material of the toxicants and act as susceptibility factors. Small clinical microorganisms in the body) represents a third priority area studies using antibiotics or microbiome transplant support of inquiry. There is increasing evidence for links between a potential role for microbial imbalance in contributing to the gut microbiome, brain, and behavioral phenotypes the cause of core ASD behaviors. Taken together, these 133,134 relevant to ASD. The microbiome is also emerging as data suggest possible linkages among exposures, microbiome an important component of response to environmental function, and ASD phenotypes. This is an area that has exposure. Studies have demonstrated persistent changes in only begun to receive research attention which should be the function of the microbiome after exposure to immune expanded in the foreseeable future.

RESOURCES TO ACCELERATE ENVIRONMENTAL RISK AND GENE-ENVIRONMENT RESEARCH

BROAD DATA AND RESOURCE SHARiNG The development of consensus data standards will make it possible for investigators to consider, at the outset of As the number of studies focusing on environmental a study, inclusion of common environmental measures/ risks for ASD increases, attention to broad data access and standards.139 Use of low burden exposure measures, sharing becomes critical for enabling reuse and extracting such as those available through PhenX140 or the Early Life the maximal value from the data that have been collected. Exposure Assessment Tool (ELEAT), enable genetics Consideration of privacy and consent issues in environmental researchers to enrich their analyses to account for health data is needed to ensure the development and environmental contributions to risk. Increased sharing implementation of policies that protect privacy while of study-specific exposure instruments and methods ensuring the value of shared data. Combining data across is another area of need. The National Database for observational studies can yield increased power and Autism Research (NDAR) currently provides a robust strengthen generalizability, yet heterogeneity of the types platform for making data – particularly data in standard of exposure measures used creates challenges for both formats – easy-to-find and accessible. Implementing meta-analyses and pooled analyses of primary data. On the common data standards for exposures could facilitate other hand, when different types of measures of exposure the incorporation of these type of data in NDAR. in different studies all lead to consistent findings, that consistency alone increases confidence in the conclusions.

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In addition, genetic databases including MSSNG and the iNTERDiSCiPLiNARY TRAiNiNG AND Autism Sequencing Consortium (ASC) are anticipated to CAREER DEVELOPMENT provide mechanisms for expanded data libraries to include The workforce needs related to environmental research key environmental variables, allowing for assessment of in ASD align with an increasing recognition that solving gene-environment interactions. Recent findings108,111 complex questions will require team science approaches. illustrate the benefits of incorporating environmental Programs and opportunities that train scientists and information in large data resources. With regards to support research and networking programs in ways that mechanistic tools, new models of ASD, especially those encourage crosstalk and coordination of efforts spanning with distinguishing genetic mutations of interest, should cellular and molecular neurobiology, toxicology, genetics, be made widely accessible to researchers. This can epidemiology, and exposure science are needed. Training include, but is not limited to, sharing breeding pairs of opportunities should be created around novel statistical animal models with commercial vendors for their widespread and big data approaches geared toward complex exposure distribution. Finally, to realize the potential impact of data data, with the goal of accelerating analyses that address sharing, efforts must be put into the analytic approaches multivariate risk. needed to make gene-environment discoveries from the aggregation or collective analysis of large heterogeneous data sources. Efforts that encourage methodological development as well as bioinformatics implementation and secondary data analysis funding will be necessary.

PUBLIC HEALTH IMPLICATIONS

COMMUNiCATiON AND DiSSEMiNATiON to observational studies means that results of a single ACTiViTiES FOR ENViRONMENTAL study require additional independent studies for replication RiSK FiNDiNGS and assessment of generalizability. Conflicting findings among studies are common, and may reflect spurious The multivariate risk structure of ASD, with many factors results or an unappreciated dependency of the association contributing modest risks, and different combinations of on other factors. Additionally, it is particularly difficult to risks likely to operate in different individuals with ASD, separate the effects of some exposures from other factors, presents challenges for communicating findings to affected due to inherent collinearity – for example, distinguishing families and the broader public. Epidemiologic studies true medication effects from effects due to the underlying that report associations of specific exposures with ASD health condition for which medication was required. at the population level can lead to serious misinterpretation For these reasons, communicating environmental and if extrapolated to individual cases, and a focus on individual genetic findings in ASD requires careful attention to context, risks can mask the importance of exposures whose including providing information about the strength of any modification could have substantive impact when measured newly reported finding on the scale most appropriate for across the population. Moreover, the limitations inherent the audience, the difference between cause and association,

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the specific potential limitations of any individual study including the possibility of unmeasured confounding, the population attributable risk, and the need for additional studies to confirm the association.

SUMMARY

In many cases, risk factors for ASD are shared by other disorders, and additional research is needed to ensure that corresponding public health efforts will have broad utility for protecting health beyond the implications for autism. The hope of identifying and understanding ASD risk factors is that they can be mitigated to reduce ASD-related disability.

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OBJECTIVES

OBJECTiVE 1: Strengthen understanding of genetic risk and resilience factors for ASD across the full diversity and heterogeneity of those with ASD, enabling development of strategies for reducing disability and co-occurring conditions in ASD.

Examples:

• Understand the contribution of regulatory and other genomic regions to ASD risk. Whole genome sequencing will begin to illuminate the role of non-gene coding regions of the genome.

• Identify additional autism risk genes but also contribute to an understanding of the common variant patterns that enable expression of the mutations.

• Understand the causal relationship between identified ASD risk genes and clinical outcomes so that guidelines for genetic counseling can be illuminated. Understand parental concerns and attitudes when communicating complex genetic information.

OBJECTiVE 2: Understand the effects on ASD risk and resilience of individual and multiple exposures in early development, enabling development of strategies for reducing disability and co-occurring conditions in ASD.

Examples:

• Understand the timing of exposures relative to the cascade of events that unfold during brain development to identify and understand the molecular basis of exposure-associated ASD risk.

• Conduct multiple studies in different populations and settings, with high-quality measures of exposure and adequate controls, to reconcile disparate findings and establish robust linkages of environmental exposure to ASD risk.

• Refine more targeted, conventional exposure assessment tools to characterize the exposome.

OBJECTiVE 3: Expand knowledge about how multiple environmental and genetic risk and resilience factors interact through specific biological mechanisms to manifest in ASD phenotypes.

Examples:

• Develop low-burden exposure measures that can be incorporated in large-scale genetic studies, perhaps leveraging innovations in exposomics or epigenomics.

• Move beyond identification of genetic and environmental risk factors to reveal functional biological consequences associated with these risk factors.

• Integrate methylation, exposure, and phenotype data in the same population.

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43 QUESTION WHICH TREATMENTS AND 4 INTERVENTIONS WILL HELP? 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Aspirational Goal: Develop a range of targeted treatments and interventions that optimize function and abilities across the lifespan to achieve meaningful outcomes and maximize quality of life for people on the autism spectrum.

INTRODUCTION

The evolution of this Aspirational Goal reflects comparative efficacy studies, and implementation science the progression of priorities in the autism community. studies that consider child outcomes as well as best Over the past several years, the IACC’s focus has shifted from implementation practices. Additionally, the diversity of “preventing disabilities” (2009 IACC Strategic Plan), to study participants has improved, as researchers more often encouraging “building adaptive skills” (2013 IACC Strategic strive to include underserved families as well as populations Plan Update), and now emphasizes the construction of previously excluded or overlooked in ASD research, such lifespan approaches and utilization of more meaningful as girls and minimally verbal children. treatment outcomes for individuals living with ASD and their families. This change also underscores the shifting There has also been much progress in brain-behavior landscape of treatment opportunities driven by exciting measures as predictors of outcomes of interventions, discoveries from cognitive neuroscience, which reveal as well as the development of adaptive interventions, breathtaking developmental reorganizations of brain function recognizing that sequential and multiple interventions in adolescence and young adulthood,1,2,3 adding new are often required to improve child outcomes. Finally, possibilities for intervention and learning across the lifespan. technology has been used more frequently, as a tool within an intervention (such as iPads for communication and Since the 2013 IACC Strategic Plan Update, there has storyboarding), to deliver interventions using telehealth been an explosion of behavioral intervention studies and methods, and to collect data in real time that can be used advancements in intervention science, including continued to guide intervention and gauge treatment response. progress in the development and evaluation of multiple intervention types. Key advances include improvements The next generation of more precise, personalized in community implementation of effective interventions, treatments and interventions will be developed with the greater numbers of fully powered randomized trials, benefit of the knowledge gained from neuroscience and

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genetics research on the systems biology of ASD. Researchers treatments, and intervention approaches that match the are now utilizing the latest discoveries and tools from needs of individuals with ASD. Great progress has been these fields to develop and evaluate genetically targeted made, and will continue to be made, by prioritizing the pharmacology, neuroimaging-guided direct brain stimulation, understanding of the brain basis of ASD and biological combination drug (or brain stimulation) and behavioral mechanism(s) underlying a given therapeutic approach.

INTERVENTION AND TREATMENT TYPES

The autism community continues to emphasize the BEHAViORAL iNTERVENTiONS importance of establishing evidence-based practices in Behavioral interventions fall into two broad classes: focused interventions.4 Evidence-based practice is grounded on intervention practices and comprehensive treatment models the premise that there are interventions that have evidence (CTMs). Focused intervention practices are instructional of their positive and strong effects for individuals with or therapeutic approaches applied to an individual’s ASD, and that practitioners (e.g., psychologists, psychiatrists, goals (e.g., making social initiations to peers, reducing speech pathologists, teachers) should therefore prioritize self-injury), designed to produce outcomes related their use while working with families. When strong evidence specifically to the goal, and are implemented over a for an intervention or treatment to address a specific goal relatively short period of time until an individual meets or outcome does not exist, the practitioner should try the his or her specific goal. Meanwhile, CTMs address broader intervention with the most evidence, although the empirical outcomes (e.g., increases in cognitive abilities, adaptive efficacy may fall below an established standard. Clinical behavior, social and communication skills). CTMs consist of and/or professional expertise plays a major role in selecting many focused intervention practices organized around a an intervention or practice to address a specific goal or more conceptual framework, are documented through treatment generalized outcomes and is especially useful for adapting protocols, and exist over a more extended time period. the intervention for the individual with ASD when needed. Examples include the Lovaas Model5 and the Early Start 6 Looking forward, advances in neuroscience and genetics Denver Model (ESDM). that provide knowledge of the biobehavioral mechanisms Practitioners use these two classes of interventions/ of treatment efficacy (summarized in Chapter 2 of this treatments in different ways. They may select multiple report) support a new principle to guide evidence-based focused intervention practices to build individualized practice: Preference should be given to those treatments programs for children, youth, and adults with ASD, or they and interventions for which there is a current or emerging may fully adopt a comprehensive treatment program in understanding of the biobehavioral mechanism(s) of action. which the focused interventions and their use are already This will facilitate highly innovative, randomized, experimental prescribed.7 Although several CTMs have been shown to therapeutics trials in human participants. Such trials will be efficacious, they may be implemented less often by improve our understanding of the developmental mechanisms practitioners than focused intervention practices.8,9 The underlying ASD risk and resiliency, thereby enabling the National Standards Project and the National Professional development of novel treatments and intervention strategies.

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Development Center on ASD (NPDC) have conducted of ASD and pave the way for more school-based critical and rigorous reviews of the intervention research intervention research. literature and identified sets of focused intervention practices that have evidence of efficacy.10 Parent-Mediated Interventions As diagnostic advances have made it possible to identify children with The NPDC work specifically focused on practices that ASD at earlier ages, researchers have tested a number of could be implemented in school and/or community settings. parent-mediated interventions in order to meet the need for Similarly, deBruin and colleagues conducted a meta-analysis interventions that can be implemented as early as possible. of school-based interventions in high schools, finding Most of these are labeled Naturalistic Developmental evidence of efficacy for many of the same focused Behavioral Interventions (NDBIs), a newly vetted grouping intervention practices (i.e., antecedent-, video-, and of early interventions based on applied behavior analysis consequent-based interventions).11 Other reviews have (ABA).29 Several recent studies have yielded significant documented the efficacy of 1) school-based, focused improvements over earlier studies by comparing interventions on challenging behavior, 2) the use of peer- the experimental treatment to an active control group networks to foster social engagement, 3) social skills training, involving parent education but no hands-on coaching, and 4) academic interventions.12,13,14,15,16,17 Research on versus comparing an experimental treatment to the efficacy of several behavioral interventions continues treatment as usual.30,31,32 today, including the Lovaas Model, ESDM, JASPER (Joint Attention, Symbolic Play, Engagement, and Regulation), One conclusion of these recently completed studies LEAP (Learning Experiences and Alternative Program for is that active hands-on parent coaching for social Preschoolers and Their Parents), PRT (Pivotal Response communication outcomes is more effective than parent Treatment), First Words Project, DIR/ education models where the same information is provided (Developmental, Individual-Difference, Relationship-Based), without active coaching. This conclusion is further supported EMT (Enhanced Milieu Teaching), and STAR (Strategies for by another recent study of toddlers at risk for ASD, Teaching based on Autism Research).5,6,18,19,20,21,22,23,24,25,26 finding that initial gains in parent responsiveness did not sustain to the follow-up, speaking to the need for longer-term, School-Based Interventions It can take over a decade more intense, or more hands-on intervention.33 A recent and a half for evidence-based interventions to become widely parent-mediated intervention study based on the DIR/ implemented in the community when developed in the Floortime intervention approach suggests efficacy of this laboratory. Thus, researchers are increasingly developing model for improving parent and child outcomes.22 and testing interventions in school-based settings, with Researchers have also studied the benefits of parent group the added goal of sustaining the intervention beyond the interventions, where groups of parents are coached to deploy study period. Two recent studies demonstrate that similar interventions. In a recent study of the PRT approach, outcomes can be obtained in the community and the researchers found that parent group interventions yielded lab.27,28 Both of these studies implemented JASPER aimed significant parent and child benefit.34 While more cost at improving core impairments in social communication, effective than 1:1 therapy sessions, more research is needed and noted sustainability of the intervention over a short-term to determine the generalizability and sustainability of parent follow-up. As a whole, these and other findings highlight group interventions to foster meaningful improvement in the effectiveness of teacher-implemented interventions child behaviors, communication, and functioning. in school settings on improving one of the core features

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Altogether, the foregoing studies add to the positive through models that matched the child’s communicative outcomes attained through parent-mediated interventions intent. This may have provided the combination of supports but raise issues about meaningful outcomes (i.e., spontaneous needed for minimally verbal children with ASD to versus prompted outcomes) and the specific “active successfully increase their spoken communication. Earlier ingredients” – or essential components – of treatment access to speech-generating devices along with naturalistic (i.e., hands-on coaching, dose, approach). In the future, behavioral interventions at the start of treatment may be researchers will need to better understand for whom most beneficial to minimally verbal children. This is an an intervention works best, and why an intervention area that demands much greater research attention. provides benefit. Understanding the mechanisms behind effective behavioral interventions helps researchers to Girls with ASD are another understudied and identify the essential components of an intervention, making underserved group. Recent studies find subtle but important it possible to develop a repertoire of components that can developmental differences between preschool-aged boys 37 be combined in various ways to customize treatment. and girls with ASD. Studies of older children find girls Two recent studies suggest that parent synchronization with ASD who have lower IQs also have more impairing (attuning of the parent’s behavior to the child’s attention) symptoms of ASD than boys. Girls with higher IQs report and mirrored pacing (following the child’s lead) are better friendships and social skills and fewer repetitive 38 important components or active ingredients of parent- behaviors than boys. School playground observations of mediated interventions.35,36 girls with ASD find they are overlooked and neglected by their classmates in more subtle ways, whereas boys with Behavioral Interventions in Understudied ASD are often overtly rejected.39 In part, these differences Populations Developing interventions for minimally between girls and boys with ASD are due to the ability of verbal children has been very challenging. A recent study girls to camouflage their interaction difficulties.40 These tested whether JASPER combined with a behavioral findings suggest that gender should be included as a language intervention with or without an augmentative tailoring variable when individualizing interventions for and alternative communication (AAC) device facilitated children with ASD. greater spoken language over 6 months.32 This study took an adaptive treatment approach, adjusting the treatment Groundbreaking brain imaging and genetics studies midway through the study based on an individual’s progress. have revealed important differences between males and The results of this study suggest important implications females in the brain and genetic mechanisms underlying about the treatment approach and timing of providing an autism. For instance, genomic studies have provided AAC device in treating minimally verbal children with ASD. tantalizing evidence for a “Female Protective Effect” (FPE) hypothesis in ASD,41 such that a greater amalgamation For instance, the approach focused on developmental (more and/or more intense) of risk factors is necessary pre-requisites to spoken language, including joint attention, in females versus males to lead to autism. To illustrate, joint engagement, and play along with systematic deleterious copy number variations (CNVs) are three times modeling and prompting for spoken language. more likely in autistic females than in males.42 Furthermore, The researchers utilized a developmental, child-directed recent gene expression work from postmortem brain approach with strong naturalistic reinforcement strategies. samples demonstrates that autism risk genes, rather than Adults were contingently responsive to child attempts being sexually dimorphic themselves, interact with pathways at communication and provided expansion of language and cell types that themselves are sexually dimorphic.43

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Looking ahead, as it is becoming increasingly clear that While the majority of such trials are testing pharmacological females and males with ASD differ in terms of causes, treatments, neurostimulation (discussed separately below) developmental profiles, and symptom profiles, we need is also gaining momentum as a modality to alter brain to understand how they respond differently to treatment activity and neuronal connectivity, as is the development approaches. At present, there are no adequately powered of approaches based on stem cell technologies. studies that focus on sex differences in behavioral and/ or neural-systems-level treatment response. Such studies There has been an abundance of open-label, single-center should be a major priority for the research community. drug trials that report effectiveness in small samples. Unfortunately, many of these results were not replicated Discoveries of neuroplasticity in the adult brain have when tested in subsequent larger, randomized, placebo- opened new opportunities to consider autism interventions controlled trials. Many of the drug trials in ASD exclude for use in adulthood. Very few studies of behavioral individuals with intellectual disability and very young children interventions have been performed in adolescents or adults due to ethical and/or practical challenges. However, a with ASD, and most of these have focused on training mechanism-based intervention intended to improve core adults to read social cues.44 Executive and social brain symptoms of ASD may be more effective if administered networks exhibit the greatest rates of functional maturation relatively early in life and may be most effective in those during adolescence, establishing adolescence and young most severely affected. Thus, it is crucial that such individuals adulthood as a sensitive period for socio-emotional and are included in upcoming trials. This will require researchers self-control development.45 These new findings suggest to carefully consider how interventions can be adapted to that the period from adolescence into young adulthood accommodate children or individuals with intellectual may offer an important new window of opportunity for disability, and to identify age- and ability-appropriate individuals with ASD, their families, scientists, and clinicians outcomes and outcome measures. Additionally, researchers to design novel approaches for improved outcomes and must ensure that parents and families are well-informed superior quality of life. and actively engaged through all stages of the trial.

MEDiCAL iNTERVENTiONS Many different genes may contribute to the susceptibility of developing ASD. This heterogeneity of underlying causal Pharmacological Treatments In contrast to the mechanisms makes it challenging to identify convergent many behavioral intervention options available, only two molecular pathways and brain circuits involved in all drugs, and , currently have Food individuals with ASD, although there has been recent and Drug Administration (FDA) indication for use in ASD, progress. One promising target is oxytocin, a neuropeptide specifically for the symptom of irritability. There are no involved in social cognition that has been investigated in approved treatments for the core symptoms of ASD, which a number of ASD studies.46,47,48 However, its molecular include social communication difficulties and restricted, properties pose challenges for potential therapeutic use; repetitive patterns of behavior, interests, or activities. thus, further work is needed to determine the best doses Although clinical trials of pharmacological interventions and compare methods of delivery. Moreover, given the for core symptoms of ASD are now underway, they will variation of oxytocin’s effects based on behavioral context, require several years for completion, analysis, and reporting; studies aimed at understanding how oxytocin might thus, there are few published findings to date. Advances in enhance responses to evidence-based behavioral genetics and neurobiology have led to an increase in the interventions are recommended.49 number of clinical trials testing medical treatments for ASD.

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Other randomized, placebo-controlled treatment trials may be due, in part, to the difficulty in assessing anxiety have targeted additional mechanisms proposed to symptoms in autism and to the inappropriate stratification contribute to the pathophysiology of ASD, with varying of appropriate subjects. When individuals with and without successes.50,51,52,53,54 N-acetylcysteine (NAC), an antioxidant anxiety are grouped together as the "experimental" group, treatment, was well-tolerated and had the expected effect it is often difficult to attain a high enough level of response of modulating oxidative stress markers, but had no impact to consider the trial a success. This is an issue that relates on social impairment in youth with ASD.50 D-cycloserine, to all treatment trials of the co-occurring conditions. And, a partial agonist of the N-methyl-D-aspartate (NMDA) additional research efforts must be directed to adequately glutamate receptor, was tested in combination with social subdividing individuals with autism into more homogeneous skills training. No difference was found in the drug treatment subgroups that have common symptom profiles. group compared with placebo.51 The serotonin partial agonist buspirone was used to target core symptoms during the Given that the rates of diagnosed ASD cases are developmental period of low serotonin synthesis capacity in rising and that there are no effective drugs to treat its young children with ASD. Low-, but not high-, dose buspirone core symptoms, it is imperative to further develop showed significant improvement in a measure of restricted pharmacological treatments. Involvement of private industry and repetitive behaviors.52 Finally, a double-blind clinical trial will be crucial to help address this unmet need, including using the diuretic bumetanide that reduces intracellular in industry-academic collaborations. Important private chloride, thereby augmenting GABAergic inhibition, partners include the pharmaceutical industry, as well as those showed that bumetanide significantly reduced clinical in software, electronics, and robotics development. As much symptoms of ASD in children 3-11 years old and was as possible, multi-site, longer-duration, placebo-controlled well-tolerated.53 Furthermore, bumetanide combined with studies should be prioritized in order to produce more a behavioral intervention resulted in a better outcome in reproducible results, such that private industry will take children with ASD than a behavioral intervention alone.54 on the challenges of conducting large Phase III Larger trials are needed to validate these initial findings. registration studies. Moreover, given the importance of context and a Transcranial magnetic developmental perspective on ASD, it will be very important Direct Brain Stimulation stimulation (TMS) is a potentially promising method for to conduct well-powered studies that combine identifying neural mechanisms and treating aspects of pharmacological treatments with evidence-based practices altered brain function in ASD.62 TMS can offer a non-invasive including behavioral approaches, cognitive behavioral tool to study aspects of the altered physiology underlying therapy, and social skills training. This issue is discussed ASD. Treatment strategies involve using TMS to modulate in detail below. brain plasticity and network activity.63,64,65 In particular, A number of treatment trials are targeting the associated repetitive TMS (rTMS) can alter brain excitability and or co-occurring conditions of autism. One of the most network activity beyond the duration of a stimulation prominent is anxiety, which affects at least 40% of individ- session or treatment study, and is being examined as a uals with ASD.55 Treatments range from cognitive behav- treatment that could potentially reduce both core and 66 ioral therapy (CBT)56,57 to medications.58,59,60,61 While associated ASD symptoms. there have been some notable successes, there is also substantial variation in outcome. The variation in success

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Recent studies have investigated whether neuromodula- excessive microglial activation leading to aberrant neural tion via rTMS or transcranial direct current stimuli (tDCS) connectivity pathways.76,77 Stem cell therapies have been can induce neurophysiological and clinical benefits in shown to modulate immune activity and facilitate neural individuals with ASD.67,68,69,70,71 Preliminary results suggest connectivity and are being tested in autism populations. that TMS might be of therapeutic value for improving core and associated symptoms of ASD. However, work on brain Preclinical models have shown that umbilical cord blood stimulation as a therapeutic technique for ASD is still in contains effector cells that, through paracrine signaling, 78,79 the very earliest stages of development. There remain can alter brain connectivity and suppress inflammation. many unanswered questions and potential barriers for Infusions of stem cells in mouse models of autism have 80,81 widespread application of these techniques. In particular, resulted in improvements in autism-like symptoms. the mechanisms by which these techniques might improve In humans, infusions of autologous cord blood cells have brain and behavioral function in ASD are not yet known. been shown to be safe and beneficial in patients with cerebral 82,83,84 Most studies to date have been based on small samples, palsy and other acquired brain injuries. A Phase I, employed open-label designs, and provided mixed results; open-label trial assessed the safety and feasibility of some people with autism appear to benefit while others a single intravenous infusion of autologous umbilical cord 85 do not. There is a need for well-controlled, randomized trials blood in 25 children with ASD, 2-6 years of age. with adequate sample sizes to better understand whether Assessment of adverse events across a 12-month period brain stimulation is efficacious and safe and whether there suggested that the treatment was safe and well-tolerated. are subgroups of individuals with ASD that might benefit Significant improvements in children's behavior were from treatments based on brain stimulation. In particular, observed on parent-report measures of social one major barrier to the widespread application of brain communication skills and autism symptoms, clinician stimulation in treating ASD is the potential to cause epileptic ratings of overall autism symptom severity and degree of seizure activity, especially in people who are already at improvement, standardized measures of expressive risk for developing seizures. Epilepsy is a potentially vocabulary, and objective eye-tracking measures of children's devastating condition that is much more common among attention to social stimuli, indicating that these measures individuals with ASD, especially those people with ASD may be useful endpoints in future studies. Behavioral and lower intellectual abilities. improvements were observed during the first 6 months after infusion and were greater in children with higher baseline Stem Cells Stem cell technology has greatly advanced nonverbal intellectual ability. Double-blind, placebo- our understanding of typical and atypical neurobiological controlled studies of the efficacy of umbilical cord blood processes, thereby offering new opportunities for treating for improving autism symptoms are currently underway. neurodevelopmental disorders including autism. Increasing evidence suggests that the pathophysiology of autism may As with brain stimulation, this research is only just involve neuroinflammation, at least in a subgroup of cases.72 beginning, and there are many hurdles to overcome and Immune pathology in individuals with ASD is evident in unanswered questions to address before the field will overexpression of immune-related gene networks in know whether stem cell techniques can provide safe and postmortem brain tissue,73 presence of maternal antibodies useful treatments for ASD. This will be an important area to fetal brain tissue,74 atypical levels of proinflammatory of investigation to monitor as researchers work to cytokines (IL-6, TNF-α) in the cerebral spinal fluid,75 and replicate and expand these initial, encouraging findings.

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TARGETiNG SPECiFiC BiOLOGiCAL manipulating faulty copies of the MECP2 gene, transcript, MECHANiSMS or protein is an appealing approach for treating RTT. Read-through strategies as well as gene transfer approaches The prospect of precision medicine in ASD, i.e., specific, using adeno-associated viral vectors are being actively targeted treatments developed after gaining a better pursued. understanding of specific disease pathophysiology, is a tantalizing one. Genetically defined disorders such as FXS is an X-linked, trinucleotide repeat expansion disorder Rett syndrome (RTT), Fragile X syndrome (FXS) and involving the FMR1 (fragile X mental retardation 1) gene. tuberous sclerosis complex (TSC) provide a unique This is a leading single-gene cause of ASD. The FMRP opportunity to develop mechanism-based treatments for protein encoded by this gene regulates protein synthesis ASD. Thanks to basic science discoveries describing the in neurons. Advances in our understanding of the patho- molecular pathogenesis of these disorders, researchers physiology of FXS have led to the development of numerous have begun efforts to evaluate treatments targeting targeted trials. The most prominent theory of FXS, the 86 specific proteins in the implicated biological pathways. metabotropic glutamate receptor (mGluR) theory, posits In future work, biomarkers should be incorporated in order that many symptoms of FXS are due to exaggerated to help detect objective improvements in response to responses to activation of mGluRs. The prediction of this treatment and to identify optimal developmental periods model was that reduced activation of mGluR would to apply the treatment trials. remedy the symptoms of FXS. However, recent clinical trials (Phase II and III) with two different mGlu5 inhibitors The most common cause of classic RTT is a de novo (basimglurant and mavoglurant) showed no therapeutic in the X-linked gene MECP2 (methyl-CpG-binding protein 2). benefit in FXS patients for reasons that are as yet unclear.91 MECP2 mutations are inherited in X-linked dominant fashion, Driven by lessons learned from previous trials of mGluR and females are almost exclusively affected. In light of antagonists, investigators are planning a multicenter the basic science discoveries in the pathogenesis of RTT,87 placebo-controlled trial of mavoglurant for children with researchers have proposed multiple routes to treatment FXS ages 2 ½ to 6 years of age. This trial will examine for the disorder based on knowledge of MECP2 function. outcome measures, including language, for all participants These strategies are designed to address either the with a parent-implemented language intervention underlying gene defect or downstream pathways implicated provided to all participants and psychopharmacologic in the disorder. Clinical trials are underway evaluating intervention provided only to some.92 the use of two different NMDA receptor antagonists, dextromethorphan and ketamine, to improve outcomes Approximately 50% of the patients affected with TSC 88 like epilepsy in RTT. Among neurotrophic factor effectors also develop ASD, and 90% will have seizures sometime 89 downstream of MECP2, IGF-1 has been studied. in their life. Importantly, many patients with TSC will be Double-blind, placebo-controlled trials of rhIGF-1 and diagnosed with this disease very early in life, usually in the NNZ-2566 (a synthetic version of the terminal tripeptide newborn period, due to the presence of heart tumors. fragment of IGF-1) have recently finished and are being This provides the unique opportunity to investigate the prepared for publication. The cholesterol pathway has development of ASD in this high-risk group during the 90 recently been identified as being involved in RTT, and first year of life. A recent study shows that an abnormal lovastatin is currently under investigation in an open-label electroencephalography (EEG) signature has 100% positive trial for females with RTT. Finally, directly or indirectly predictive value for clinical seizures, 2-3 months prior to

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the onset of these seizures.93 These data have led to the TECHNOLOGY-BASED iNTERVENTiONS initiation of a “prevention” trial in the high-risk infants with Digital-based technology interventions for individuals TSC using the anti-seizure medication vigabatrin. TSC with ASD have continued to increase in accessibility, patients have hyperactivation of the mTOR pathway, which breadth, and depth of use. Scientific evidence for the controls neuronal protein synthesis similar to FMRP. The effectiveness of technology-based or technology-enhanced hypothesis that overactive mTOR signaling in TSC may be interventions has increased, with a larger number of ran- amenable to mTOR inhibitors has led to trials involving the domized controlled trials (RCTs) appearing in recent years use of this class of medications in patients with TSC. A large that highlight the breadth of technology applications in Phase III trial demonstrated that adjunctive mTOR inhibitor ASD research as well as their increasing rigor.95 In the field treatment was effective for refractory focal epilepsy in TSC of robotics, recent work has highlighted potential advan- patients.94 Whether mTOR inhibitors will also be effective tages of robots over human agents for accelerating several in improving neurodevelopmental symptoms including ASD aspects of intervention research. Yet a number of challeng- is not yet known. A Phase II trial was recently completed; es and gaps have been highlighted, which are also shared results are pending. by speech-generating devices, virtual reality, Taken together, advances in the study and treatment video games and computer-assisted instruction, mobile 96,97,98 of RTT, FXS, and TSC have laid the groundwork for similar applications, and telemedicine. It will be essential mechanism-based treatment trials in genetic disorders for future studies to address these challenges, as the associated with ASD. Translating successes from animal development of interventions using digital technologies studies have not been straightforward to date. offers new opportunities to accelerate research progress. Intellectual disability commonly affecting individuals Furthermore, the proliferation of technology-based with these neurogenetic disorders is an additional platforms purporting to help individuals with ASD points obstacle in study design in this field. Next steps will to a need for new, efficient, and scalable methods and need to include biomarkers to help detect objective infrastructure for evaluating technology-based interventions. improvements in response to treatment and to identify Technology-based interventions have tremendous potential optimal developmental periods to apply the to benefit individuals on the autism spectrum in many treatment trials. ways, including by helping them improve social and communication skills and gain greater independence, all of which can improve the overall quality of life.

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OUTCOME MEASURES AND BIOMARKERS

Over the past few decades, significant progress has been Biomarkers of treatment success are needed, as are made in the development of new behavioral interventions “stratification” biomarkers for matching people to the best and identification of novel drug targets aimed at reducing treatment for them at the best time. For example, while core and associated ASD symptoms and improving quality oxytocin (OXT) has been a promising target for treating core of life across the lifespan. A major challenge in determining social communication symptoms in ASD, trials have not whether new treatment approaches are efficacious has produced consistently positive or negative results. This is been the measurement of treatment response. Measurement widely thought to be due to genetic and phenotypic of treatment response is particularly complex in ASD heterogeneity among trial participants who nonetheless due to the heterogeneity resulting from an individual’s all receive the same diagnostic label of ASD. A recent symptom profile, sex, cognitive and language abilities, and study demonstrated the potential for pretreatment blood development level. Moreover, many existing assessment levels of OXT to serve as a stratification biomarker. measures were developed for screening and diagnosis Individuals with the lowest pretreatment blood OXT and are not sensitive to assessing change in symptoms concentrations benefited the most from intranasal OXT over time. administration.105 Until it becomes possible to biologically measure treatment response, negative results from Considerable effort has been directed toward evaluating pharmacological and behavioral interventions will be difficult which existing measures are suitable for clinical trials to interpret, and positive results may not definitively indicate and for developing quantitative, objective, and sensitive the requisite dose or duration of treatment. Predictive measures of treatment response. Increasingly, the input biomarkers (those that help to match individuals to particular of key stakeholders, including caregivers and persons on treatments) will help to create more precise treatments the autism spectrum, is solicited to ensure that outcome and help individuals with ASD and their families to avoid measures reflect the priorities and needs of persons for wasted time and resources. which the treatments are being developed. Several reviews and consensus statements have been published that have BiOMARKER DiSCOVERY evaluated the appropriateness of existing parent report Initial efforts have focused on developing measures that and observational measures for clinical trials, including are linked indirectly or directly to underlying neural circuitry, measures of social communication, anxiety, and repeti- which can offer insight regarding whether the treatment tive behaviors.99,100,101,102 Studies validating observational is influencing specific aspects of neural circuitry, inform measures of ASD symptom severity based on the Autism researchers of the neural mechanisms that might underlie Diagnostic Observation Schedule (ADOS) have also the treatment effects, and predict treatment response. been published,103 and a brief observational assessment These measures include eye tracking, electrophysiological of social communication change has also been recently responses, and magnetic resonance imaging, among others. developed.104 Such measures can also serve as an early efficacy signal that can detect response to treatment before changes in

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more distal measures such as language and social abilities with ASD associated with specific genetic syndromes. are evident. Early efficacy markers can be used to identify In future work, prior to these measures being useful as which individuals are most likely to benefit from a given potential biomarkers, it will be important to demonstrate treatment and/or in adaptive study designs to indicate their ability to reliably predict a signature of dysfunction early in the trial whether modifications in the treatment at the individual subject level, as opposed to group (e.g., dose) should be made. averaged data.

Eye Tracking (ET) ET has great potential for acting as Magnetic Resonance Imaging (MRI) MRI techniques, an early indicator of treatment efficacy by tracking changes including functional MRI (fMRI) and Diffusion Tensor in social attention.106 While applications of ET to clinical Imaging (DTI), have provided a wealth of information trials and interventions are still relatively new, results regarding the neurobiological underpinnings of ASD. have been encouraging and suggest that ET can be used Specifically, task-based fMRI studies have pointed to as a method for measuring response across a wide range atypical social-brain functioning and activation in ASD, of treatments. Promising future directions for developing while resting-state functional MRI and DTI have pointed ET as a marker of change include: furthering data-driven, to deficiencies in integrative social information processing computational, and machine learning approaches towards as indicated by white matter atypicalities and diminished subtyping and stratification within the autism spectrum long-range connectivity.108,109 Despite the potential for and for improved discrimination between individuals with brain imaging techniques to elucidate mechanisms ASD and controls; the design of ET batteries with the underlying behavioral treatment response, few studies express goal of treatment measurement; the adaptation have directly used it for treatment monitoring or prediction and advancement of ET metrics in technology-driven/ of treatment efficacy. However, this appears to be rapidly technology-interactive interventions, such as virtual changing, with several recent studies expanding on earlier reality, robotics, and simulators, as well as in novel adaptive work.110,111 Considerable progress has also been made paradigms designed to change gaze strategies; and recently in regards to the use of brain imaging techniques advancement of methodological considerations including for understanding in vivo pharmacological neural action the promotion of big data studies, facilitation of replication, in individuals with ASD. Altogether, these advancements and increasing adherence to more rigorous and universal are beginning to provide the context for expanding the technical and methodological standards. scope and applicability of brain imaging techniques for monitoring treatment across the lifespan, including before Electrophysiological Measures Recent studies the signs of ASD are overtly apparent. Given the many suggest that EEG, a non-invasive measure that can record successes yielded from the application of MRI methods to patterns of brain activity throughout the lifespan, offers the development of biomarkers in ASD and related fields, promise as a metric of treatment response related to neural considerable opportunity exists for further research and 107 circuitry. Children and adults with ASD have distinct development in this area. electrophysiological signatures, offering the possibility of using such measures to detect treatment response. Advances in Developing Measures of Treatment Furthermore, distinct EEG signatures have been found Response Digital technologies, such as mobile devices, among genetic subtypes of individuals with ASD and provide another approach for developing quantitative, related disorders, and these signatures could be used in objective, and sensitive measures of treatment response.112 future clinical trials to test drugs targeted to individuals These tools provide opportunities to study biomarkers in

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combination with self-report data, often in more naturalistic of de-risking investments into pharmacological ASD trials contexts such as the home. The ability of technology-based and optimizing the success of such trials. These projects systems, such as mobile applications, wearables, and are examining a wide range of potential biomarkers and internet resources, to automatically record and generate their relationships with observational and caregiver-report data will increasingly provide richer, denser, and more measures of behavior in large samples of individuals with meaningful information to researchers. Novel analytic ASD versus typical development over time. Furthermore, methods, such as machine learning and computer vision regular communication, data sharing agreements, and analysis, can provide new insights into patterns of behavior. shared measures across the existing consortia will increase Although early in their development and application to ASD the scientific utility of these investments. One example populations, such measures have the advantages of being is ABC-CT (Autism Biomarkers Consortium for Clinical scalable, objective, and feasible. Thus, studies that explore Trials), a National Institutes of Health (NIH)-, Foundation their utility as a method of treatment monitoring should be for the NIH-, and Simons Foundation-funded consortium pursued. Additional emphasis should also be placed on of sites that aims to develop, validate, and disseminate transforming these signals into useful forms to maximally aid objective measures of social function and communication and personalize ongoing, real-world treatment of issues faced for ASD with the ultimate goal of advancing these measures by individuals with ASD. As the understanding of these data as markers and predictors of treatment response. streams matures, new methods and systems will need to be created to harness the power of this data and to manage the In sum, multiple laboratories are conducting studies to massive flows of information reaching data consumers. develop better ways of measuring treatment response. Continued investment in such studies will ensure that, as Recently, a number of substantial investments have been new behavioral and medical treatments are developed, made to support large, collaborative efforts aimed at we will have the capability of testing their efficacy. Such validating biomarkers and outcome measures for use in investments will also be essential for developing improved ASD clinical trials. These consortia involve public-private methods for identifying subgroups that are responsive to partnerships among academia, advocacy and other non- specific treatments and identifying neural mechanisms profit organizations, government, and industry, with a goal underlying treatment response.

INNOVATIVE COMBINATIONS OF THERAPEUTIC MODALITIES

There are now tremendous opportunities for combining have not been responsive to drug therapies yet. But, the therapeutic modalities in ways that allow for positive possibility of combining drugs with behavioral interventions impacts from the amalgamation that are greater than the still holds promise for improvement in these core areas. sum of the parts. One example would be the combination A few of these studies are in progress, but none have been of psychopharmacology and behavioral treatments. The reported during this review period. core impairments of ASD (e.g., social communication)

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Advancement of new or reconceptualization of existing Similarly, adaptive interventions, which incorporate more treatments into modular therapies (where therapies are flexible study designs, can make more efficient use of existing organized into therapeutic modules that can be combined clinical, research, and participant resources, providing more and reused in flexible arrangements) can provide information to researchers and potentially greater benefit finer granularity and more tractable opportunities for to participants. To encourage adoption, investment in understanding change in individuals. This is an area of study design methodology research (including dissemination great need and can especially help address co-occurring of methods and development of trial design resources) conditions, such as anxiety, aggression, and depression. will be of significant value.

ACCELERATING RESEARCH AND INCREASING ACCESS TO EVIDENCE-BASED INTERVENTIONS

While research in interventions for individuals with provide more comprehensive information about treatment autism has shown consistent growth and advancement, effectiveness when clinical uncertainty is matched with opportunities exist for accelerating the pace of research. appropriate variation along key implementation parameters. First, high-quality intervention studies are expensive to Similarly, sharing data at finer level of detail may additionally conduct and require substantial specialized expertise to facilitate data mining investigations that may help to identify oversee. Additional investment in human and research more streamlined assessment or nuanced precursors and infrastructure is likely to yield compounding gains in autism predictors of treatment response. intervention research progress. Creating and sustaining networks of institutions, investigators, clinicians, and Further resources should be directed towards promoting families committed to shared, large-scale implementation the development of applied scientific tools, including more of interventions or experimental research will combat robust statistical methods, data mining techniques, basic fundamental heterogeneity issues in ASD research, leading science methods, laboratory techniques, and optimized to more reproducible and robust scientific findings. These pipelines for discovery. Additional resources could also be networks can be leveraged to promote testing of novel spent at the tail end of intervention science, on the wider interventions, exploration of unique scientific perspectives, dissemination of implementable discoveries. Examples and commitment to a culture of non-exclusive innovation would include encouraging Phase II transitions to Phase transcending traditional boundaries. Additional investment III trials, identifying appropriate industry partnerships to should focus on bridging gaps between scientific evidence foster larger-scale intervention implementation, and in vivo and clinical and/or community applications of interventions. studies of ongoing new intervention integration efforts. Incorporation of business and operations perspectives Additional opportunities may emerge from standardization into autism research infrastructure development may help of reporting and protocols so as to facilitate aggregation to optimize intervention deployment efficiency, enabling or comparison of clinical trial data at meta-analytic levels. more studies to be conducted in a sustainable fashion. Examination of evidence at a higher analytical level may By focusing on practical barriers to ultimate treatment

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deployment (including insurance, provider adoption willingness, and marginal expenses), a more robust, efficient, and complete pipeline from idea to effective individual treatment can be realized.

INCLUSION AND EMPOWERMENT OF STAKEHOLDERS IN INTERVENTION RESEARCH

Empowering individuals with ASD and their families to act as rights) would further enable stakeholders to direct their active directors in the research process can also accelerate research agenda. Adaptation of stakeholder-held records, scientific progress. Development of tools to help stakeholders including genomic information, for the purposes of creating manage and maintain research, educational, behavioral, an interface that would facilitate recruitment of participants and clinical records could help them better advocate for with extremely specific characteristics (e.g., pharmacological participation in studies most relevant to their needs or most trials targeting specific gene mutations) may be critical for aligned with their personal goals. With a focus on usability appropriately powering highly targeted studies and for and controlled data sharing, such tools could become providing stakeholders access to the most tailored and interfaces by which information could be bi-directionally innovative science.113 Throughout the research process, shared with researchers and relevant providers, reducing the involvement and feedback from the autism commu- redundancy in information requests, streamlining study nity should be emphasized so as to provide continuous deployments, and reducing participant burden. context for research endeavors.

Currently, several incarnations of such systems have been Much more attention has recently been given to quality developed, including Microsoft HealthVault and Apple of life outcomes for addressing the needs of individuals HealthKit. However, efforts towards tailoring interfaces, with ASD, including: academic success, autonomy and cross-platform interoperability, and common standards self-sufficiency, financial stability, health and well-being, must be pursued so as to best meet the specific needs of inclusion, independent living, meaningful employment the autism community, to prevent data from becoming with fair wages, pursuit of dreams, recreation and leisure, unnecessarily locked to proprietary platforms or formats, respect and dignity, safety, self-identity and acceptance, and to better enable data exchange. Creation of user-friendly social connections, and subjective well-being. Using such research registries that promote awareness of relevant outcomes allows professionals, parents, and individuals ongoing intervention studies or technologies, that can be to develop intervention plans that will allow a person with personalized by user preferences (including constraints ASD to advance daily in each of the quality of life indicators. on geography, participation characteristics, and study facets), Measuring such outcomes can occur both in the short- and that are updated regularly and managed in a sustainable long-term and can be developed based on the needs of the fashion, and that facilitate connections between individual in terms of their level of skills, functioning, and legitimate researchers and qualified research participants ability. When such indicators are maximized, the individual (with appropriate governance of privacy and participant will be able to fully live a life maximizing long-term success.

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SUMMARY

While there have been multiple, important advances in approaches. More robust, standardized outcome measures the field of autism interventions and treatments, there is still should be developed, including adaptive measures, predictive much progress to be made. Researchers must continue to measures, biologically based metrics, measures that develop new treatments as well as adapt existing treatments address heterogeneity, and measures of practical outcomes for diverse settings and populations, including males and and quality of life that will help better target therapies females, individuals with co-occurring conditions and to individual needs and goals. It will also be important to varying levels of ability across multiple domains, individuals study combination therapies that mimic how therapies across the lifespan, and those in settings or communities may be delivered in real-world settings, and that offer the that are under-resourced or underserved. Moving forward, opportunity to provide greater benefits than any individual there are several important issues to consider. First, it will therapy alone. To realize the goal of developing the next be important to leverage advances in our understanding generation of ASD therapies, funders will need to devote of the neuroscience and neurobiological mechanisms significant investment to building and enhancing the research underlying all therapeutic approaches. Second, researchers pipeline to train of the next generation of multidisciplinary need to consider designs and recruitment strategies that intervention scientists. Finally, it will be essential to allow for testing ways to maximize effectiveness and provide more tools to practitioners through translation precise matching of treatment plans to individual needs of research to community-based practice and to deploy and neurobehavioral profiles by combining therapeutic effective, novel dissemination strategies.

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OBJECTIVES

OBJECTiVE 1: Develop and improve pharmacological and medical interventions to address both core symptoms and co-occurring conditions in ASD.

Examples:

• Advance the study and treatment of genetic syndromes related to ASD, including RTT, FXS, TSC, and utilize the groundwork provided by investigations of these disorders to develop similar mechanism-based, genetically targeted pharmacology treatment trials for ASD.

• Explore innovative treatment modalities and combination therapies.

• Develop therapies to address challenges across the spectrum and across the lifespan.

• Investigate treatment response, including how females with ASD respond differently to treatment approaches, with a focus on the use of cognitive neuroscience tools to examine alternative mechanisms of change underlying symptom change.

• Develop biomarkers that can help inform decisions about the most appropriate interventions for particular individuals from across the autism spectrum and provide objective, early assessments of treatment response, prior to overt symptom change.

OBJECTiVE 2: Create and improve psychosocial, developmental, and naturalistic interventions for the core symptoms and co-occurring conditions in ASD.

Examples:

• Support research to ensure that interventions include the whole autism spectrum and diverse populations, including females, minimally verbal individuals, intellectually disabled individuals, adults, and individuals in under-resourced and underserved communities.

• Leverage the neuroscience of neuroplasticity of the adolescent and adult brain to develop psychosocial interventions targeting these age groups, meeting their specific needs, offering a path toward continued development of life skills, and enhancing quality of life.

• Define the “active ingredients” of successful therapeutic approaches as a basis for future innovation and tailoring of interventions to particular populations or settings.

• Explore combination therapies.

• Develop outcome measures that include biomarkers of treatment success, measures of improvement across multiple domains, and improvements in quality of life.

60 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

OBJECTiVE 3: Maximize the potential for technologies and development of technology-based interventions to improve the lives of people on the autism spectrum.

Examples:

• Develop tools allowing individuals with ASD to track and direct their own treatment.

• Develop technology-based interventions that help people with ASD improve their social and communication skills, increase their independence, and in many other ways help improve the quality of their lives.

• Develop interventions for minimally verbal children and those with intellectual delay, with a focus on the use of technology to augment communication (for minimally verbal children) as well as adaptive, individualized treatment approaches for both groups of underserved children.

• Increase access to interventions by developing technology-based treatments that can be deployed outside of primary care or clinical settings.

61 WHAT KINDS OF SERVICES AND QUESTION SUPPORTS ARE NEEDED TO MAXIMIZE QUALITY OF LIFE FOR 5 PEOPLE ON THE AUTISM SPECTRUM? 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Aspirational Goal: Communities will develop, access, and implement high-quality, evidence-based services and supports that maximize quality of life and health across the lifespan for all people with ASD and their families.

INTRODUCTION

In previous editions of the IACC Strategic Plan, Question 5 For example, the U.S. Government Accountability Office (Services) addressed access and coordination of services (GAO) released two reports, the first entitled Youth with for individuals with ASD and their families. Research Autism: Roundtable Views of Services Needed during the on services and supports focuses on self-directed care, Transition into Adulthood in 20163 and the second entitled coordination of funding and services among state and local Federal Agencies Should Take Additional Action to Support agencies, community-based supports, and the need to Transition-Age Youth,4 that described the needs of youth better measure the health, safety, and mortality of people with ASD transitioning to adulthood and ways in which with ASD. Previous Question 5 Strategic Plan objectives Federal agencies might fill current service gaps. included support for research to develop and evaluate the New research on the cost of ASD across the lifespan has training of service providers who work with individuals contributed to the knowledge base around ASD services. with ASD, and to improve the efficacy, cost-effectiveness, Researchers estimate that the lifetime cost of supporting dissemination, and implementation of evidence-based an individual with ASD without intellectual disability in the practices. In 2015, 6% ($21 million) of ASD-related research United States is approximately $1.4 million.5 Contributors to funding from Federal agencies and private organizations total costs for children with ASD were direct nonmedical addressed issues related to services.1 A lack of sufficient costs, such as special education (including early intervention funding raises considerable barriers for researchers to services), and indirect nonmedical costs, such as parental develop, test, and implement service system delivery models productivity loss. For adults with ASD, contributors include that increase the supply of care and address the gaps accommodation (residential care or supportive living between research and practice.2 accommodation), direct medical costs, and individual productivity loss. Others studies show that caring for a child There have been several notable positive changes over with ASD can cost over $17,000 per year more than caring the last few years regarding services research and planning, for a child without ASD, with 18% of these costs associated particularly due to an increased focus on the needs with increased use of healthcare services.6 of individuals with autism as they age out of childhood. 63 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

While these studies highlighted some of the areas in which In this chapter, we describe gains and opportunities in the needs of individuals with ASD are not being met, specific service-related areas. For all the recent successes they have not defined solutions. Adequate, cost-effective in ASD services research, gaps in services remain for services are still lacking, as are strategies to decrease children and adults with autism and their families. financial stress for families.

PROGRESS IN THE FIELD

EDUCATiON SYSTEM Center on ASD have demonstrated improved outcomes when students are the recipients of evidence-based Most school-aged children with autism receive the practices, and they have begun to develop practices to majority of their ASD-related services through the public assist with the scale-up of these interventions. Unfortunately, education system.7 The number of children receiving these implementation of evidence-based practices remains the services, as well as the cost of their education, is increasing. exception rather than the rule; implementation of innovative A growing body of research suggests a nationwide problem interventions is challenging due to limited fit with classroom of ineffective educational programming and the need for needs and lack of professional support. New research in stronger educational workforce development, support, implementation science highlights the need for a systems training, and supervision. With relatively little research on approach that includes involving leadership in and across developing specific guidance for addressing challenges schools to develop a strong culture and climate for within the education system, it is necessary for educators quality implementation. working with students on the autism spectrum to address the complex and growing set of challenges. Our definition of autism and our understanding of how autism co-occurs with other mental health challenges While Federal and state legislation has placed a greater has expanded. Eighty percent of students with ASD have focus on accountability and performance standards, there co-occurring physical or mental health challenges,8 requiring is little agreement or standardization of how performance new education strategies and coordination across multiple should be measured. The No Child Left Behind Act and service systems. Recent research has focused attention the Individuals with Disabilities Education Improvement Act on co-occurring anxiety9,10,11 and depression,12,13 as well as (IDEA) both state that students with ASD must have suicide risk.14,15,16,17 Models for recognizing and addressing access to high-quality, research-based interventions these challenges in schools have not yet been developed that help keep them in the least restrictive instructional or disseminated. environment that can meet their learning needs. National programs such as the SWIFT (School-Wide Integrated Many schools have not fulfilled the promise of educating Framework for Transformation) Center have documented children with autism in the least restrictive and most change strategies and instructional approaches that can integrated environment suited to their needs. While be used to meet these legal requirements. Federally funded several models of inclusion have demonstrated efficacy,18 programs such as the National Professional Development the type and quality of inclusion programming to which

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children with ASD have access is highly reflective of local appropriate mental health, developmental, and specialty policies, resources, and expertise rather than reflective of health services. In 2014, the Centers for Medicare and evidence-based practices grounded in research. There is Medicaid Services (CMS) issued guidance affirming the also a need for quality interventions to help keep children applicability of EPSDT standards to the treatment of with ASD in an instructional environment that maximizes ASD. Outside of Medicaid, there are large disparities in their potential; because of the range of learning styles of insurance coverage and reimbursement rates based on children with ASD, students often need options such as differences in state health coverage mandates. The effects distance learning and smaller group instruction. of the discrepancies in billing rates and reimbursement prevent implementation of evidence-based practices and Currently, the public education system is not adequately interventions for individuals with ASD and their families. preparing all children with autism for adulthood. Although there have been improvements in recent years, approximately There is a continued need for ASD insurance reform. half of students with ASD leave secondary school without Families of children with ASD who have a medical home – employment or plans for further education.19 While much a partnership with their primary care doctor to provide of school programming is focused on those who will attend personalized treatment plans - report fewer unmet needs college, this is not an option for many students with ASD, and more shared decision making with healthcare who will also leave school without the skills needed to providers.20 The Affordable Care Act (ACA) of 2010, Section enter the workforce. During the transition to adulthood it 2703, created an optional Medicaid State Plan benefit for is important to teach youth with autism the social and states to establish Health Homes to coordinate care for vocational skills necessary to have successful outcomes people with Medicaid who have chronic conditions. While after leaving the education system. ASD is not a chronic condition listed in the statute, it is subject to state application, then review and approval. HEALTHCARE SYSTEM State ASD insurance mandates increase ASD diagnosis and treatment rates by 13%, after controlling for other There has been considerable progress in some areas of variables.21 This effect increases the longer the insurance ASD services-related research within the healthcare system. mandates are in place. However, the number of children One important funding stream for reimbursement of services receiving ASD services is still fewer than would be expected provided to individuals with ASD is the Medicaid program. given current prevalence estimates, though this does not Jointly operated between the states and the Federal control for public versus private service utilization. government, Medicaid provides healthcare coverage for individuals below certain income thresholds and Mounting research shows that Medicaid Home and encompasses a wide array of benefits, such as case Community Based Services (HCBS) waivers can management; physical, occupational, and speech therapies; significantly meet the service needs of people with ASD and rehabilitative services that are often used by individuals and decrease their unmet healthcare needs, especially with ASD. The Early and Periodic Screening, Diagnostic among those who would not otherwise qualify for and Treatment (EPSDT), the child health portion of Medicaid.22 Those with ASD who access services through Medicaid, mandates the provision of medically necessary waivers are also less likely to use inpatient and long-term services found at section 1905(a) of the Social Security services care.23 Since 2010, CMS has undertaken several Act to Medicaid beneficiaries under the age of 21. activities that have provided new information about ASD EPSDT ensures that children and adolescents receive

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services available in the community. Among these is a report seizures, and metabolic disease, among other conditions.29 published in 2014, Autism Spectrum Disorders (ASD): State To address these significant health disparities, it is of the States of Services and Supports for People with ASD, necessary to increase implementation of services and which assesses existing state programs and supports for evidence-based approaches in addition to research to families living with ASD in all 50 states and the District improve services for co-occurring conditions. of Columbia.24 This CMS study provides a comprehensive view of services that received support from various Federal Wandering behavior presents additional safety risks sources and were made available through state programs for some individuals with ASD. Recently, the National across the country. Autism Association (NAA) released a report stating a third of reported ASD wandering/elopement cases in the APPROPRiATE SERViCES TO ADDRESS United States were either fatal or required some level of HEALTH AND SAFETY CONCERNS medical attention, while encounters with water, traffic, and other threats accounted for an additional 38% of Recent studies have shown that people on the autism cases.30 Among emergency care visits, adolescents with spectrum are at increased risk of many health challenges ASD accessed emergency department services four times and premature mortality.17,25 Research is needed to both as often as adolescents without ASD.31 There are also understand what causes poor health and safety outcomes disparities in emergency department visits among children and to develop strategies to improve outcomes. Among with ASD living in rural areas compared to urban places.32 the most pressing health concerns for children and adults Ensuring broad access to services through more innovative diagnosed with ASD is ensuring adequate support to strategies is necessary to close the gaps in health and address co-occurring conditions, which may include mental safety for children and people with ASD. One strategy that disorders, sleep problems, gastrointestinal disturbances, or has seen success is ECHO Autism, a University of Missouri other issues.26 Unfortunately, there is a lack of understanding telehealth program aimed at reducing wait times and and awareness among service providers regarding the improving primary care for children with autism living in challenges these conditions pose to individuals with remote areas.33 The program has seen success in Missouri ASD and their families.27 This often leads to a lack of and plans to replicate and expand the model to isolated appropriate services and multifaceted interventions. areas throughout the country and world. Parents of children with ASD and co-occurring psychiatric conditions are more likely than other parents of children The healthcare system needs to emphasize increasing with ASD to report that their child’s needs are not being access in underserved populations and increasing met.26 A broad assessment of mental health, learning, cultural competency among service providers. The literature and cognition problems associated with ASD is crucial to suggests disparities in utilization and access to healthcare determine appropriate services and treatments for people and educational services for those with ASD from minority with ASD throughout the lifespan.28 populations and families from lower socioeconomic status (SES).34,35,36,37,38 Ethnic minority children with ASD tend There is mounting evidence that these co-occurring to receive diagnoses almost one year later than White conditions contribute to premature death among children and often receive fewer specialty services.39 individuals with ASD. A Swedish study showed that the Despite initiatives to increase the quality of healthcare average death for an adult with autism is 54 years, and provider interactions with families of children with ASD that loss of life years is mostly attributable to suicide,

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and developmental disabilities, the health service systems (e.g., choosing roommates, choosing day activities) do not meet the needs of minority populations.40 Disparities compared with those without autism. Also, fewer adults in access and utilization may be due to the lack of cultural with autism were legally independent adults without competency of providers, perceived low quality of care, guardianship (37%) than were adults without autism (53%). or the lack of family-centered care, among other factors.35 While research has been funded to assess variations in and In recent years, there have been greater efforts to advocate access to services in relation to health disparities, the for use of person-centered planning models, particularly in research needs to be taken a step further to study how to Federal service systems. Medicaid-funded HCBS waivers address what we have learned. We need to better understand are required to be furnished according to a person-centered what portfolio of services will result in the best outcomes plan of care, reflecting the services and supports that are for diverse populations. important for the individual to meet needs identified through a functional assessment, as well as what is important to Overall, it is important to continue to support research to the individual in terms of preferences for the delivery of test quality services and supports as well as evidence-based those services and supports. However, there are interventions that can eventually be implemented in a many individuals with ASD who are not using HCBS community setting and be accessible through medical waivers but still need the right tools and services to achieve coverage. A systematic, evidence-based, collaborative person-centered care throughout their lifespan. While approach can facilitate the scaling up of evidence-based research has identified some of the barriers to person- practices in community settings.41 Factors identified to aid centered planning, the services community has yet to in scaling up evidence-based interventions in community develop successful strategies to ensure individualization settings are organizational support and readiness, program and choice for individuals with ASD to lead independent and implementer characteristics, and sustainability and meaningful lives. planning.42 CAREGiVER SUPPORTS ENSURiNG iNDiViDUALiZATiON, Caregivers may experience significant levels of stress CHOiCE, PERSON-CENTERED PLANNiNG, as they support an individual’s needs and manage medical AND SELF-DiRECTiON and therapy appointments, while also engaging in work and Often, service systems approach the needs of individuals other responsibilities.44,45 The high cost of services also with autism as one-size-fits-all, yet the heterogeneity of creates increased financial strain for families, who often are autism requires different supports for different people. the main caregivers across the lifespan. Families often Individuals with ASD and their families want to be able to need respite services to be able to take care of themselves, make choices about their lives and actively engage in the have breaks from caregiving, and increase their own social planning of their services and supports. According to a and emotional well-being so they are in turn able to support National Core Indicators survey, the number of adults and care for their family member with ASD.46 Also, respite with autism receiving services through developmental care has been shown to reduce hospitalizations among disability (DD) agencies increased from 10% to 15% children with ASD.47 Mindfulness-Based Stress Reduction between 2008/2009 and 2013/2014.43 Further, of the interventions have been shown to be helpful for families adults who used DD services, those with ASD had of individuals with disabilities, but those studies have significantly less input into all measured life choices primarily focused on families of children.48

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Parent education about autism and parent training focused 2015 study had unmet service needs during the last year on teaching behavior management strategies are both of high school, with 30% having three or more unmet effective in reducing disruptive behavior – with parent training needs. Specific needs included career counseling/job skills having a slight advantage in one study.49 More research is training and life skills training. Youth with autism without needed regarding the effectiveness of these services for ID were far less likely to receive these services. Barriers different parent populations and across different types of included cost, geographic access to services, and lack of parent educators. providers who accepted their insurance.

Further, studies are needed to examine the transition of Results from the Autism Needs Assessment care from parents to other family members, once parents survey, which represented people with autism ages 2-59 are no longer able to provide care. There is a rich history of years indicated that, compared to other age groups, adults caregiver transition research among adults with intellectual received fewer services for their specific unmet needs disability, but little is known about how this process occurs in social skills training (43%), speech-language therapy in families caring for a relative with ASD. (22%), individual supports (21%), and occupational therapy (21%).53 Focus groups of Pennsylvania adults with ASD OUTCOMES, QUALiTY OF SERViCES, who use Medicaid-funded services and those who care for AND SERViCE NEEDS them identified a specific set of needs: training (co-occurring diagnosis, sexuality, long-term planning), community One size does not fit all when addressing unmet service engagement (individualized community activities geared needs. Even though parents from both low- and high-income to interests of individuals), socialization, and employment.54 homes have awareness of their child’s service needs, parents from lower-income homes report more barriers to The complex needs of the service system make it difficult to accessing services. Specifically, they report needing more sustain implementation science. For example, organizations information about services and more in-home services, trying to implement evidence-based practices might not while higher-income parents report needing higher-quality be able to maintain the cost to fund these services and services.50 supports long-term. Current and future research initiatives need to consider improving the service infrastructure. Despite public investment in special education, studies show high rates of disconnection from jobs and continued HOUSiNG, SUPPORTS, AND OTHER education after high school. Of young adults who were SERViCES ACROSS A CONTiNUUM OF not working or attending school, 28% also received no SEVERiTY AND NEED ASD-related services.51 Overall, one-fourth (26%) of young adults with autism received no services between Residential services, postsecondary education, employment high school and their early twenties.51 supports, behavioral and communication supports, lifetime learning supports, and other services are discussed in A qualitative study of service receipt and unmet service more detail in Questions 4 and 6 of the Strategic Plan, but needs during the last year of high school found that youth they are important to mention here in that these services with ASD in this cohort were receiving fewer services must also be provided based on the continuum of severity than youth with ASD captured in earlier data from the and need, and they must be integrated with other services Department of Education’s National Longitudinal Transition as part of a coordinated system of services and care for 52 Study-2 (NTLTS2). Two-thirds of the sample from the individuals with ASD.

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WORKFORCE there is not funding to support coordination or an assigned liaison. There are other systematic barriers for families Underlying many of the challenges described in the such as differences in the type and amount of services above sections is the lack of a well-trained, supervised, and supported by insurance plans and the inequities and motivated workforce. Several studies have documented disparities in type and amount of services available among practitioners’ insufficient use of evidence-based practices geographic location. in community settings, as well as the difficulties associated in implementing these practices because practitioners lack Individuals with autism often require services provided appropriate pre-service training and preparation, oversight through different agencies and paid for through different in the field, or a sense that the use of these practices is systems. Care delivered across these systems often is 55,56 expected, supported, and rewarded. The field of inefficiently and ineffectively coordinated. Some of the implementation science has begun to address how to challenges are endemic to systems that are providing care impact practitioner behavior through organizational change concurrently (e.g., the education and healthcare systems); and direct-to-practitioner support. However, these other challenges are endemic to hand-offs between strategies do not address more fundamental issues related systems as individuals age out of one set of programs to attracting highly qualified individuals to relevant into another. professions, creating pre-service training programs that prepare individuals to deliver evidence-based care, and Some service models have been shown to promote better keeping individuals in the field once they complete their integration of care. For example, health home models and education and/or training. medical home models provide conceptual frameworks to coordinate and integrate services, as well as build systems COORDiNATiON OF SERViCES of care for persons with ASD and their families.57 Use of these models is not widespread, however, nor do these There is also a need for systematic analyses of the models address a host of other coordination challenges. complexities of accessing the service systems. While there For example, analysis of the National Longitudinal Transition is a lack of research in this area, families face multifaceted Study-2 found that only 58% of youth with ASD reported challenges to access services that often delay the receipt of having received a transition plan by the Federally required early intervention services for a child. Expansion of Section age.51 The transition plan is a critical document that offers 2703 of the ACA to include ASD and other developmental a template for coordination between the school system disabilities may increase the number of families who and systems that serve adults. In a 2012 report, GAO found have a medical provider and a medical home and improve that youth and their families faced challenges in identifying, access to and coordination of care. Coordination of service navigating, and establishing eligibility for services for sectors is urgently needed. Also, families must deal with adults with disabilities, including autism58 (GAO-12-594). different sources of funding for services, frequently with The same report found that adult service systems did different for who, what, and how many services not routinely provide a coordinated plan of services or can be provided, with no clear sources of information objectives for youth making transition to adulthood. about what these sources are and how they interact. The There is a particular gap in implementing and evaluating different service sectors are not coordinated and often the coordination between policy and practice for the do not communicate with each other, particularly across services needs of individuals with ASD. health and social service agencies. In most instances,

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SUMMARY

There are many opportunities for increased investment in required scale to meet community needs. There also needs ASD services research to fill important gaps in knowledge to be an understanding of what portfolio of services will about what services are needed, how to best deliver result in the best outcomes for diverse populations. More them, which services work for which communities, and innovative research approaches and the resulting data will strategies to increase implementation of best practices be needed in the future to support progress toward the across settings. The Committee continues to highlight IACC Question 5 Aspirational Goal of creating an the need for researchers to focus on developing practical, environment where "communities will develop, access, affordable, and culturally competent services and support and implement high-quality, evidence-based services and approaches that can be used in a variety of settings, and supports that maximize quality of life and health across for these approaches to be able to be adapted to the the lifespan for all people with ASD and their families.”

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OBJECTIVES

OBJECTiVE 1. Scale up and implement evidence-based interventions in community settings.

Examples:

• Identify best practices, including systematic evidence-based collaborative approaches, to scale up existing services and increase access to evidence-based interventions in communities.

• Test and implement cost-effective healthcare services that increase the supply of care.

• Develop approaches that scale up the use of evidence-based practices in the educational setting and address the gaps between research and practice.

• Funding for provider training is a part of Question 7 Objective 2, but is cross-referenced here because successfully growing the service workforce is necessary to achieve this objective to successfully scale up and deliver evidence-based ASD interventions.

OBJECTiVE 2. Reduce disparities in access and outcomes for underserved populations.

Examples:

• Support research to understand and develop strategies to address health disparities, health inequity, and disparities in services access and utilization for underserved populations. Underserved communities include families with low socioeconomic resources, youth and adults with severe intellectual impairment, those who are racial/ethnic minorities, and women.

• Develop culturally competent service provision strategies, improve the quality of care and perception of quality of care to encourage utilization, and increase family-centered care as well as other best practices to reduce disparities.

OBJECTiVE 3. Improve service models to ensure consistency of care across many domains with the goal of maximizing outcomes and improving the value that individuals get from services.

Examples:

• Develop better metrics and measurement tools for health outcomes of people with ASD across the lifespan.

• Develop, test, and implement metrics and measurements for ASD services, as well as Federal, state, and local programs.

• Quantify outcomes in order to inform effective service models.

• Continue research into determinants of service quality, including accessibility, continuity, and flexibility of services.

71 QUESTION HOW CAN WE MEET THE NEEDS OF PEOPLE WITH ASD AS THEY PROGRESS 6 INTO AND THROUGH ADULTHOOD? 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Aspirational Goal: All people with ASD will have the opportunity to lead self-determined lives in the community of their choice through school, work, community participation, satisfying relationships, and meaningful access to services and supports.

INTRODUCTION

Each year in the United States, approximately 50,000 of physical and mental health disabilities. However, we individuals with autism spectrum disorder (ASD) turn 18 also know that some individuals with autism do experience years old.1 According to 2016 Centers for Disease Control and positive outcomes. Little progress has been made in Prevention (CDC) data, prevalence of ASD in 8-year-olds understanding how best to support these individuals and rose dramatically from 1 in 150 in 2002 to 1 in 68 in 2012.2 their families so that good outcomes are the norm rather The 2002 cohort is now 23 years of age. Thus, across the than the exception. This leaves providers and policy makers next decade, we can expect a 123% increase in the number with an absence of evidence-based knowledge to use of youth with an ASD diagnosis exiting secondary school. when deciding which services, supports, and programs There are significant concerns about how this increase will will be most beneficial to adults with ASD, and few affect the transition and adult disability service systems. resources to implement those programs. Research to understand the unique needs of this growing population is urgently needed in order to develop services The increasingly influential voice of the self-advocacy and programs that facilitate opportunities for people on the community has highlighted the vast heterogeneity in autism spectrum to lead fulfilling, self-determined lives. strengths, impairments, and functioning among adults with ASD. Thus, real progress toward achieving the Aspirational Since the 2013 IACC Strategic Plan Update, there has been Goal is even more challenging than previously thought, as continued progress in understanding adult life for those on it is highly unlikely that any given service or program can the autism spectrum. Nearly every study finds that adults effectively meet the needs of all adults with ASD. Yet, with ASD have difficulty accessing disability and medical these same voices also highlight the many and varied ways services, experience high rates of unemployment and that adults with ASD can make rich contributions to society, underemployment, face difficulties in daily living skills and making it even more imperative to understand how to achieving independence, and contend with elevated rates support them in achieving their highest potential. 73 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

It is important to note that nearly every study cited in extent these findings apply to individuals in mid- or the following sections focuses on early adulthood and the later-adulthood, from racial/ethnic minority groups, or transition years, and utilizes samples with little racial/ with fewer socioeconomic resources. ethnic or socioeconomic diversity. It is unclear to what

PROGRESS IN THE FIELD

TRANSiTiON TO ADULTHOOD not those typically provided by disability services, such as supports for living on campus or living independently, The years immediately prior to the 2013 IACC Strategic Plan training to engage in self-advocacy, and interacting effectively Update – from 2010 to 2013 – were instrumental to with peers and instructors.11 For students with ASD who demonstrating the challenges faced by youth with ASD and have significant mental health concerns, intensive services their families during the transition out of secondary school addressing emotion regulation in addition to the and into adult life. Studies during this time demonstrated organizational and social skills necessary for college success high rates of unemployment and underemployment,3,4 may be needed. For students with co-occurring intellectual difficulties accessing services,5 disconnection from friendship disability, a college-like transition program with a focus and social activities,6 and the negative impacts of secondary on independent living skills may be appropriate. school exit on behavioral development.7 Little has been published on issues related to community Increasing access to vocational rehabilitation (VR) services participation, such as housing, social participation, and for adults with ASD has not significantly improved community integration, since the 2013 IACC Strategic Plan employment outcomes across the last decade; only one- Update. There is some evidence to suggest that youth with third of adults with ASD receiving VR services achieve ASD tend to become more isolated from structured social/ successful employment.8 These adults earned lower wages recreational activities in the community after leaving and worked fewer hours than other young adults with secondary school.12,13 This may be problematic for many, disabilities receiving services. Thus, even when receiving as the presence of meaningful daytime activity is a key services, employment outcomes are poor for young contributor to quality of life.14 While no new data has been adults with ASD. published on housing for people with ASD since the 2013 IACC Strategic Plan Update, the most recent study Pursuing postsecondary education can be important in found 87% of young adults with ASD lived with their fostering independence, self-determination, and employment parents or guardian after high school and only 19% had success. Greater numbers of individuals with ASD lived independently.15 are seeking higher education opportunities in vocational/ technical skills, 2-year colleges, and 4-year colleges/ There is a growing number of small intervention trials, universities.9,10 Yet, fewer than half of college students with funded through the National Institutes of Health, aimed ASD feel they are able to handle most of the challenges at smoothing the transition process and improving adult they encounter.1 The types of needed supports identified outcomes for people with ASD. Targeted initiatives by individuals with ASD in higher education settings are

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responsive to objectives in the previous IACC Strategic Plan Given the high level of need, many publicly and privately are supporting many of these new interventions. Ongoing funded initiatives are in place to improve post-secondary studies are testing programs to: improve transition planning educational and employment participation and retention. in schools; train parents how to advocate more effectively College support programs for students with ASD are for adult disability services;16 improve family climate developing across the country, and college and universities through group psychoeducational intervention;17 target without these programs consistently express a need for self-regulation and social competence among college greater ASD-related support services. Yet, the effectiveness students with ASD;18 improve employment supports;19 of these post-secondary education and employment increase social skills,20 and build job interviewing skills programs is almost never evaluated. It is important to and customized employment supports.21,22,23 Those determine which of these many initiatives are producing interventions that show promising initial results ideally positive results and for whom, so that an evidence base can will be tested in large-scale randomized controlled be developed to guide service providers and policy makers trials, with the ultimate goal of incorporating them into as they are deciding which programs to implement. intervention options to improve adult outcomes. Many of the cohort studies that inform our knowledge Despite these promising new directions for research, base about transition and adult outcomes involve samples important gaps in knowledge remain. First, much of our of individuals who were diagnosed with ASD 20, 30, or even information about the transition to adulthood comes from 40 years ago.24,25,26 With the many fast-moving initiatives large, population-based studies such as the National around transition services and supports, community Longitudinal Transition Study-2 (NLTS-2). These studies employment, and access to post-secondary education, it have provided seminal information about the range and is unclear whether the post-school activities of youth with scope of needs of youth with ASD exiting secondary ASD who left secondary school 10 or more years ago are school in the United States. Yet, the measurement in these representative of today’s youth. Thus, it will be important datasets does not have the detailed, personalized information to follow existing cohorts in the future, as well as needed to provide targeted recommendations to disability continue to develop and follow new cohorts of youth with service workers on college campuses, parents who ASD as they transition to adulthood. This combination want their sons and daughters to succeed in college or of strategies will allow us to understand development employment, or adults themselves who are searching for throughout adulthood, and ensure that recommendations the most appropriate services and supports based on for transition-related interventions and services do not their unique situations. Coupling high-level snapshots like reflect outdated needs of individuals and families. the NLTS-2 with “deep-dive” data collection into the lives of adults with ASD of all ages will likely provide the LiFE COURSE OUTCOMES BEYOND best evidence about how to support these individuals. TRANSiTiON: EMPLOYMENT, VOCATiONAL Furthermore, the ASD community could benefit from a close SKiLLS, AND COMMUNiTY iNTEGRATiON examination of research and services strategies that have Although most studies on adult outcomes since the last been effective with other vulnerable youth (e.g., exiting IACC Strategic Plan update have focused on the foster care) and adult (e.g., those with severe mental illness) transition years, a handful have examined outcomes beyond populations to identify policy and practice approaches early adulthood. Discoveries in the employment realm that could be adapted for people on the autism spectrum. have centered on understanding patterns over time.

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For many people with ASD, maintaining work or post- commuting to work and traveling to school, healthcare secondary educational positions once they are obtained services, and community life activities. Yet, evidence to is a significant challenge.27,28 The few studies that have support the development of targeted programs and support examined employment beyond young adulthood do not is woefully lacking. Families and corporations are leading find patterns of improvement over time; most adults who the way in innovations to find and sustain meaningful are unemployed or underemployed in early adulthood employment and community housing for adults with ASD, tend to stay that way, and independence in vocation- but further research as well as state and Federal government al positions declines over time for some.25,29 Also, many programs are needed to address current and future needs. adults with ASD are working in segregated work settings. In 2014, the Workforce Innovation and Opportunity Act The heterogeneity of ASD traits and severity for those on (WIOA) was signed into law to help increase competitive the spectrum necessitates a variety of housing options to employment opportunities for individuals with disabilities. fit the specific service needs of each individual. Perhaps However, there is limited research focused on adults with by virtue of the required infrastructure, housing options ASD transitioning from segregated work settings into have been slow to respond to changing needs, values, and integrated employment. It is important to note, however, research findings regarding adults with ASD. Lakin and 30 that poor employment outcomes are not universal; some colleagues (2008) describe the national agenda to adults with ASD successfully obtain and maintain jobs. increase the number of community-based housing options Little is known about the factors that distinguish those for individuals with intellectual disabilities as a way of adults who have greater versus fewer struggles with increasing community participation and self-determined employment; those factors that have been identified are choice making. The recent final rule from CMS gives clear difficult or impossible to change, such as IQ or early preference to small, community-based homes over larger language. One notable exception is self-care skills, which congregate care settings and intentional communities. consistently predict employment and are amenable to Some advocates have hailed this ruling as a victory that intervention.3,29 There is a limited body of research will increase community participation; others, especially examining employment supports available to some adults those who care for severely impaired and medically with ASD and how they can be beneficial to maintaining fragile individuals, have expressed grave concerns that employment, such as the use of low- and high-tech appropriate care will not be available under this new assistive technologies and communication aids, natural financing arrangement. There are remarkably little data supports, and mentoring. A wide variety of employment available to support which housing options work best for service options are needed, including expanding current which individuals, with studies presenting contradictory models of job finding and development services, long-term findings regarding the level of community participation intensive services and supports, and long-term but and choice making that individuals with ASD or ID have 31,32 minimal supports (e.g., a few hours/month). in different housing options. Research is desperately needed on the most appropriate housing arrangements There is almost no research on the community participation and in-home supports, and perhaps more importantly, of adults with ASD in middle or later adulthood. The needs strategies to better observe what happens in these of individuals with ASD in terms of employment, housing, arrangements, to increase community engagement, social participation, and community integration almost and to maximize quality of life. certainly change as they age. There is also a need for research on transportation access for adults with ASD, including for

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Longitudinal studies of adults with ASD remain rare, but that takes into account the desires, skills, and abilities of those that have been conducted provide some suggestion adults with ASD and their families, then the Aspirational that many adults move into and out of “successful Goal of developing programs and supports that allow outcomes” across adulthood.25,27,28,29 To make progress adults on the autism spectrum to reach those outcomes toward the Aspirational Goal, there needs to be more will be more feasible. focus on understanding how outcomes and needs of adults with ASD change over time, and how these variations HEALTH AND HEALTHCARE compare to the general population. A one-dimensional look Current knowledge about mental health, physical health, at outcomes such as vocation, health, illness, or quality and healthcare experiences among adults with ASD is also of life at a specific point in time will not capture the rich limited. Co-occurring psychiatric conditions (i.e., two or diversity of life course trajectories. Further, it is almost more mental health diagnoses co-occurring in an individual), certainly the case that interventions and programs to known to be high among children and adolescents with improve outcomes are more or less effective depending ASD, remains challenging in adulthood. Most children with on when during adulthood they are delivered (right out of ASD who have other psychiatric disorders continue to secondary school, for example, versus later in adulthood). have at least one co-occurring diagnosis in adolescence and However, we lack the basic, large-sample, descriptive early adulthood.33 More than half of adults with ASD have studies to understand which types of interventions and at least one additional psychiatric disorder, a rate that is services might be most effective for which adults, and considerably higher than in the general population.34 when in the life course they have the most influence. Difficulties with mood and anxiety appear to be most problematic,35,36,37 and failing to address these mental Another barrier that slows progress in adult ASD research health symptoms adequately can lead to poor outcomes. is the inadequacy of current measurement tools. Without For example, individuals with ASD with higher levels valid, sensitive outcome measures, it becomes exponentially of anxiety and depressive symptoms are more likely to more difficult to detect whether an intervention or service experience difficulties in adaptive functioning.38 Even is effective and should be pursued. Further, it may be more sobering, recent research has indicated the rate of necessary to reconsider indicators of outcome altogether. suicidality is estimated to be nine times higher among Studies have typically defined what constitutes a “good adults with ASD than in the general population.39 Outside outcome” (e.g., community employment, spending time of person-level factors such as gender, verbal ability, and with friends) and thus should be the target of services and ASD severity,33,35 little is known about the full range of supports. However, it is unknown whether these outcomes factors related to stability or emergence of co-occurring are the most meaningful to individuals with ASD or their psychopathology among these adults. families. It may be that the fit of the activities to the individuals’ interests and abilities is most important, or it Co-occurring physical conditions are also a concern. may be that subjective quality of life should be an equal or Compared to adults without ASD, those with ASD have greater focus as objective indicators like employment or increased rates of common physical health conditions post-secondary education. To reach the Aspirational Goal, (e.g., sleep disorders, gastrointestinal disorders, careful research is needed to understand how to define and diabetes), as well as rarer conditions (e.g., stroke, “good” outcomes in a systematic yet personalized way, Parkinson’s disease, and genetic disorders).34 Children and and then measurement tools are needed that reliably capture adults with ASD in the United States have a higher risk of those outcomes. Once outcomes can be assessed in a way

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being overweight or obese than the general population, Relatively little is known about the aging process in people putting them at risk for cardiovascular disease, cancer, and with ASD and what types of interventions, services, and other chronic conditions across the lifespan. More work supports might foster health maintenance as individuals must be done to develop and test interventions that age. Several studies have suggested that people on the prevent, control, and/or moderate the effects of physical autism spectrum are vulnerable to premature death due and mental health disabilities.40 to a number of causes, including epilepsy, late diagnosis of medical conditions, and accidents.39,46,47,48,49 More While adults with ASD experience increased rates of research is needed to understand causal and risk factors co-occurring conditions, individuals with ASD are also at and develop strategies to prevent early death. In addition, greater risk of injuries such as falls, suffocation, drowning, research on how autism characteristics, co-occurring 42,49 and self-harm. Unintentional injuries and wandering conditions, and physical and social functioning change can often lead to premature mortality, indicating the critical during the aging process will be needed to develop 49 need for prevention programs targeting these risks. evidence-based practices to support the needs of people There is also a lack of research on understanding alcohol with ASD as they age. We anticipate that the needs of and substance abuse disorders among adults with ASD, those who are currently older adults, who may not have but this will be necessary for developing and implementing received interventions and services earlier in life, may also 41 prevention and treatment strategies. Other health be different from the needs of current youth and young concerns related to safety and risk, such as wandering adults who received different types of interventions and and victimization, are discussed later in this chapter. services in the period before reaching adulthood.50 Thus, research on current older adults with ASD and longitudinal Studies on healthcare utilization indicate adults with ASD research to follow the trajectories of youth and young utilize a disproportionate amount of outpatient, inpatient, adults will both be necessary to meet the needs of the 31,42,43,44 prescription, and emergency department services. population of adults with ASD.51,52 Only one study has examined self-reported utilization of preventive services, finding that adults with ASD were Although there is a reasonably good understanding of significantly less likely to report tetanus vaccination and the prevalence and disparities in various health states 44 pap (Papanicolaou) smears than adults without ASD. for adults with ASD, there are several gaps in this Further, adults with ASD experience more barriers to knowledge base, including how best to screen for and service use and participation in the medical visit, as well as clinically assess secondary conditions and monitor 40,44,45 lower satisfaction. Specific barriers include anxiety progress, as well as treatment dissemination and provider related to the medical visit, as well as unmet needs for training.25,53 There have been few attempts to establish additional time to process information and ask questions, the validity of instruments commonly used to assess other additional modes of communication, and reduction of psychiatric conditions in individuals with ASD. There has sensory stimulation. It is important to note that self-report also been limited consideration of differences in how is a substantial challenge for many adults with ASD when the manifestations, course, or treatment of psychiatric visiting medical settings. The physician-patient dynamic disorders might differ for these adults. Further, the majority is highly dependent upon the patient describing specific of studies on physical health needs of adults with ASD details of acute and chronic conditions, including pain and utilize retrospective point-in-time data and lack objective injury; it is often difficult for adults with ASD to engage in the same manner of self-report of medical conditions.45

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health assessment measures. Better measurement tools women on the autism spectrum may be underdiagnosed, and methods are necessary to understand the scope of and we know little about their ASD trajectories across physical and mental health needs and design appropriate the lifespan.34,57,58 services and supports. Research to improve adult diagnosis is very new and, as such, Research involving adults with ASD clearly show that there are many important gaps and areas for future study. they desire and are often capable of more independent First, there is limited knowledge of the manifestations of management of their health.44,54 To ensure these adults ASD in adults. Longitudinal studies have found that some are able to participate in their care to their fullest adults with ASD show “improvement” in autism severity abilities, the healthcare system must increase health compared to estimates obtained during earlier childhood professionals’ knowledge about ASD in general and risk or young adulthood.25,59,60 However, an extensive body of factors for co-occurring conditions. Similar to the child research has shown that ASD characteristics differ general population, providers should examine the adult’s depending on a child’s developmental stage (i.e., language general physical and mental health needs and provide and cognitive abilities, as well as chronological age), and guidance on how to ensure the person is living the healthiest the types of behaviors that best differentiate children from and highest quality of life possible. Small adjustments to neurotypical peers are somewhat different from behaviors the clinic setting (e.g., preparatory written/verbal that differentiate adults with ASD from neurotypical communication about visit procedures, private waiting peers.61,62 Thus, apparent “decreases” in autistic rooms, use of alternative forms of communication, care characteristics may simply reflect that instruments coordination, and extended time) can greatly improve designed for use with children do not adequately query the healthcare experience, compliance, and involvement the types of behaviors or deficits most relevant to adults for adults with ASD. Previous initiatives to improve care with ASD. Currently, there is not a standard tool or for those with ASD in the United States have fallen measurement used for diagnosing ASD in adults. However, short in allocating funding and provide little guidance there is an ongoing study to adapt the Autism Diagnostic regarding appropriate care for this population. Observation Schedule-2 (ADOS-2) Module 4 for use in diagnosing adults.62,63 There is also hope that work being ADULT DiAGNOSiS done to create biomarkers that predict ASD, such as perceptual computing measurements of quantitative traits, Longitudinal studies demonstrate clear evidence that will be able to be adapted as tools for diagnosing adults ASD-related difficulties persist well into adulthood. In several as well.64 Research is needed to understand how ASD cohorts of children diagnosed with ASD in early childhood, characteristics change across development and how core 80-90% of individuals continued to meet criteria for deficits manifest in adults. Studies must include consideration clinical diagnoses of ASD as adults.24,55 Simultaneously, of young, middle-aged, and older adults, including those increasing numbers of adults are presenting to clinics for diagnosed as children and those identified in later life. first-time diagnoses, and recent epidemiological work suggests that many adults with ASD may be unidentified Second, little is known about individuals who obtain and living in the community without appropriate supports.56 first-time ASD diagnoses as adults. Many of these adults In addition, as development of screening and diagnostic have other mental health concerns; in one study of young tools, as well as other autism research, has largely been adults seeking a first-time ASD diagnosis, 46% had a accomplished using data from boys and men, girls and previous psychiatric diagnosis, and 53% had contact with

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mental health services.65 These findings suggest that a SERViCE DELiVERY FOR ADULTS population of individuals with high needs is being As the research base continues to build, there are misdiagnosed or “missed” as children. Research is needed improvements in service delivery that can be made to reach to understand profiles of strengths and challenges of this the Aspirational Goal more quickly. First, it is critical that population, to inform development of screening and additional funding is provided for adult disability services. diagnostic tools and best diagnostic practices for adult Currently, waiting lists for services in most states are very ASD referrals. Such research will need to take into account long, and adults with ASD rarely receive the range and that adult psychiatric assessment traditionally relies on extent of services that would allow them to reach their self-report, whereas ASD diagnostic practices rely more potential. Adults with ASD and their families who are more on direct observation in structured clinical settings and/ vulnerable to poor outcomes in adulthood – by virtue of or caregiver report. Childhood caregivers may not be having fewer socioeconomic resources or being of a racial/ available or may have difficulty recalling specific behaviors ethnic minority group – also have the greatest difficulty occurring many decades ago. Exclusive reliance on self-report accessing needed services.3,5 It will be nearly impossible may also not be ideal, due to possible limitations in insight, to reach the Aspirational Goal of self-determination, communicative difficulties, or over-reporting of autism choice, and meaningful access to services – especially characteristics to achieve secondary gain (e.g., involvement for those who are most vulnerable – without a significant in legal system, to obtain financial assistance). investment in the quantity and quality of adult disability Third, currently it is not known if and how later-life diagnosis services and actively working to reduce barriers to access. affects mental health or well-being, or fosters identification One way to increase quality is to invest more in the training of supports or interventions. Considering that state-funded of professionals, across disciplines, to work effectively support programs often require documentation of with adults with ASD. Few adult care providers (healthcare, diagnosis prior to 18 or 22 years of age, it is unlikely that mental health, employment supports, etc.) have received someone diagnosed in middle adulthood would be able training on how to support adults with ASD. The implications to access ASD-related supports. Obtaining a diagnosis of this lack of training are far-reaching. Staff turnover is a in the absence of appropriate services and supports may significant issue in vocational and residential support be detrimental to well-being for some individuals. On the services, and likely stems (at least in part) from inadequate other hand, they may benefit from private services, training. Many adults with ASD receive their healthcare participation in online communities for individuals with in pediatric settings, due to a dearth of adult providers ASD, etc. Research in this area is needed to educate adults who feel competent and comfortable treating them. This self-referring for diagnosis about the possible benefits can pose a health risk, as pediatric providers are not and risks of obtaining an ASD diagnosis, as well as to trained to treat adult health issues. In terms of diagnostic provide insights into the types of services that should be issues, few validated screening and diagnostic instruments developed to support the adult’s integration of diagnosis are available for use in identification of ASD in adults, and into their self-perceptions. few clinicians specializing in adult screening and diagnosis are available to provide services. Neither Psychology nor Psychiatry educational programs (as well as other disciplines) are adequately preparing trainees to diagnose adults with ASD. The few programs that offer clinical rotations

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through specialty clinics often focus on persons under Elopement and peer victimization (social, verbal, and the age of 18 or 22, due to their presence in pediatric physical) are common in children and adolescents with departments. As such, there is a need for training grants ASD, but there is limited research on these topics as they and initiatives focused on training professionals who will be relate to adults.66,67 A 2012 survey conducted by the working with adults to detect, diagnose, and address mental National Autistic Society in the UK found over a third of and physical health-related needs in this population. adults with ASD experienced bullying or discrimination at work.68 A recent report suggested that, relative to adults Progress will be achieved more quickly if greater focus in the general population, adults with ASD were twice as is placed on the coordination of services between states, likely to experience sexual coercion or rape.69 Although between agencies that provide adult services, and there is some suggestion that adults on the autism between school-based and adult services. Currently, spectrum might more often be involved in the criminal Medicaid-funded services do not transfer between states, justice system, recent data from the NLTS-2 suggests that limiting people’s mobility when relocation to another state transition-aged youth with ASD were actually less likely would serve them well. Given that most adults with than those with other disabilities to be stopped by police autism have complex needs that bring them into contact or arrested.70 It might be that when they are engaged with with multiple public service systems, there is an urgent police, impairments related to ASD make those interactions need for research and initiatives focused on care more difficult, leading to negative outcomes. coordination, interagency collaboration, strategies for integrating extant funding streams, and community-based Careful research is needed to understand the experiences collective impact strategies. WIOA specifies that state of victimization in adulthood – sexual victimization, physical VR agencies must set aside 15% of their funding to provide victimization, and being taken advantage of – as well as pre-employment transition services (pre-ETS) to secondary the prevalence of other safety risks, such as wandering and school students who are eligible under either the Individuals the often adverse outcomes that unfold from wandering. with Disabilities Education Act or Rehabilitation Act Section While little is known about adults with ASD wandering 504. However, it remains to be seen if state agencies will behaviors, a recent report found 27% of adolescents be able to carry out the responsibilities associated with engaged in wandering behavior within the past year.10 legislation such as WIOA. It will be important to monitor Wandering from safe places and situations can lead to the effectiveness of these initiatives with careful data individuals with ASD being lost, missing, or injured. collection and analyses. Also, WIOA is designed to Studies are needed to understand the characteristics of encourage state-level experimentation and variability in those adults whose safety is at risk, so that preventative program design. This presents a unique opportunity to efforts can be put into place. Research focused on adults study emerging practices and capitalize on this variability in the criminal justice system is also important to to learn what works for whom. understand precipitating factors for criminality or adverse interactions with law enforcement; Helverschou et al. SAFETY, ViCTiMiZATiON, AND (2015)71 found that among criminal offenders with ASD iNTERACTiONS WiTH LAW ENFORCEMENT in Norway, 67% of crimes were related to obsessions or special interest. A recent study assessing the experiences In the past 5 years, safety issues have emerged as a of adults with ASD and police officers in England showed key concern in the autism spectrum community, yet the conflicting views on the quality of the interaction;72 research evidence on this topic has lagged far behind.

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police officers expressed satisfaction with how they appropriate supports will depend on the skills and desires had worked with individuals with ASD, whereas the of the adult, as well as the specific area being targeted individuals with ASD were largely dissatisfied with their (e.g., vocational skills versus mental health). Supports should police interaction. Research strategies to develop a better also take a lifespan developmental perspective, encouraging understanding among law enforcement might lead to less the development of new skills and abilities throughout adverse interactions and result in treatment rather than adulthood. For those adults with difficulty communicating, incarceration, which does not improve the situation parents and other care providers can play a key role in for people with disabilities. Long-term studies should also relaying their sons’ and daughters’ preferences and examine the impact of childhood victimization or other interests. Person-Centered Planning tools such as PATHs75 threats to safety, as these might lead to mental health and MAPs76 can be useful to incorporate the perspectives concerns among adults with ASD.73 Intervention studies of adults with ASD with more significant impairments. to improve awareness and safety are necessary. Further, the knowledge base about how to support There are currently a limited number of programs to improve individuals with ASD as they move into middle and later safety for individuals with ASD. In some communities, adulthood is almost non-existent. Small-sample studies policy officers and judges receive training on autism spectrum have provided some suggestion that needed supports will features, so that impairments associated with ASD are likely intensify in old age; relative to typically developing appropriately considered in interactions. Despite this, the controls, older adults with ASD experienced more severe current research is insufficient to understand the types cognitive declines in some domains and higher frequency and extent of need, or to inform evidence-based programs of Parkinsonism.77,78 Housing needs will surely intensify to ensure safety among adults on the autism spectrum. when parents are no longer able to provide care.

LONG-TERM AND CAREGiVER SUPPORTS Often families play a critical role in providing support to their adult sons and daughters on the autism spectrum. One of the best understood predictors of outcomes in Once youth with ASD leave the school system, responsibility adulthood is level of cognitive functioning: relative to those for finding and coordinating services tends to fall to parents with ASD without an intellectual disability, adults with and siblings. In many cases, adults with ASD continue ASD who have an intellectual disability are significantly to live with their parents until parents are no longer able less likely to be employed or living in the community to care for them. Even when adults live independently or (e.g., Howlin and Magiati, 2017).74 However, little is known semi-independently, parents often provide supports about how to support adults with ASD and co-occurring (e.g., financial, tangible) that facilitate the son or daughter intellectual disability in reaching their maximum potential. remaining in that residential situation. For many adults who are better integrated into their communities, high More work is needed to understand and evaluate the support needs can greatly exceed available resources of effectiveness of long-term supports for those with high family members for coordinating and organizing support needs (such as those with significant cognitive community-based life activities.12,79 Exceedingly high impairments). As many of these adults will be receiving levels of stress among parents of adults with ASD have some sort of formal adult disability service, more rapid been found via self-report measures as well as biological headway can be made in this area if service providers indicators of stress (e.g., cortisol).80 However, there systematically collect outcome data. As with other areas, are few interventions aimed at supporting families. the results will not be one-size-fits-all: the most

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Most parent-focused interventions, when their children with supporting their adult offspring with ASD, as well as in ASD are adults, provide caregivers with skills or knowledge how to provide services and supports so that families can to better support their sons and daughters, and not continue to provide care.81 These research questions necessarily to improve their own stress and well-being.16,17 become even more important in the face of an underfunded adult service system. Because housing and other adult Despite the prominent role of families in the lives of their services are limited in availability, it is even more critical adult sons and daughters with ASD, their influence is often for policy makers and providers to ensure that families are ignored in research. There is a significant research gap in well-supported so that they can continue their caregiving understanding which families are most effective in role as long as possible.

SUMMARY

To understand how to support adults with ASD, it is first funding for autism research and services focused on adults. necessary to investigate the specific areas in which adults Research focused on adult issues has lagged far behind might need supports. This is, perhaps, where the greatest other types of ASD-related research, comprising only progress toward the Aspirational Goal has been made. 2% of all autism research spending in 2015.83 We have reasonably strong evidence about the struggles Many fundamental questions about the life course that faced by adults with ASD in acquiring needed disability are unanswered among adults with ASD – such as services, accessing healthcare, finding appropriate basic understandings of how core and related autism employment or vocational activities, and achieving good characteristics, functional outcomes (e.g., employment, mental health – at least during young adulthood.3,5,26,35,38,82 education, independent living), and health change across Yet beyond basic description, there are numerous gaps in adulthood, along with the variable factors that predict knowledge that limit our ability to support these adults improving life course trajectories and quality of life – have effectively. The vast majority of what is known about been well-researched in other groups and conditions. autism spectrum disorders in adulthood has come from These questions form the necessary building blocks for samples of primarily white, middle-class, well-resourced effective and efficient interventions and services; families of males with ASD who are of average or above nevertheless, these questions can be seen as lacking average intellectual functioning. It is unclear how much of significance or innovation for those outside the autism field our current knowledge about how to achieve the Aspirational (who assume the answers are known). This can be a Goal would translate to those adults and families who are significant barrier when attempting to obtain funding for under-represented in research. Thus, studies should focus adult autism research. We will make more rapid progress on including more diverse participants, including families toward realizing the Aspiration Goal once it is clear that with low socioeconomic resources, youth and adults with a range of studies – from understanding biological and severe intellectual impairment, those who are of racial/ cognitive processes underlying outcomes, to more “natural ethnic minorities, and women on the autism spectrum. history” studies of the life course, to evaluating existing services, to intervention trials to improve outcomes – are It is unlikely that we will make meaningful progress toward critical to support adults with ASD in reaching their the Aspirational Goal without substantially increasing maximum potential.

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OBJECTIVES

OBJECTiVE 1: Support development and coordination of integrated services to help youth make a successful transition to adulthood and provide supports throughout the lifespan.

Examples:

• Use population-level data to understand unmet needs, disparities in access and outcomes, emerging usage trends, cost issues and the effectiveness of services in achieving their desired outcomes.

• Conduct research to determine the prevalence of autism in adults and the scope and distribution of service needs among the population to inform policy and program planning.

• Develop strategies for reducing socioeconomic or racial/ethnic disparities in service access and related outcomes for adults with ASD.

• Investigate social capital, the network of supports, and community integration provided by families, service providers, and others to understand the range of formal and informal supports needed to achieve successful adult outcomes.

• Develop additional service coordination across agencies (e.g., educational and vocational rehabilitation; mental health and vocational rehabilitation).

OBJECTiVE 2: Support research and implement approaches to reduce disabling co-occurring physical and mental health conditions in adults with ASD, with the goal of improving safety, reducing premature mortality, and enhancing quality of life.

Examples:

• Conduct large-scale longitudinal studies across adulthood into older age to examine trajectories of physical and mental health conditions, and address the additive and interactive effects of biological, cognitive, behavioral, and environmental factors that lead to co-occurring conditions.

• Conduct studies to improve self-management of co-occurring mental health disabilities, including anxiety, depression, and/or suicidality.

• Engage adults on the autism spectrum and their families, through collaborative and participatory research, to be involved in the development of ecologically valid measures of quality of life, which can be used to understand the factors associated with positive quality of life throughout adulthood.

• Create programs to recruit and train more general physical and mental health providers to be knowledgeable about and willing to treat adults with ASD. This applies to primary care providers, community mental health providers, and specialists.

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OBJECTiVE 3: Support research, services activities, and outreach efforts that facilitate and incorporate acceptance, accommodation, inclusion, independence, and integration of people on the autism spectrum into society.

Examples:

• Examine factors and support strategies that promote successful participation and retention in post-secondary education, employment, and/or community living activities across the spectrum of ASD and across the adult lifespan.

• Develop reliable outcome measures that take into account the desires of the individual and his/her family, as well as the match of the activity with the interests, skills, and abilities of the adult.

• Conduct long-term follow-up studies examining the effects of interventions and services delivered in childhood on later adult outcomes.

• Conduct large-scale studies of programs to improve the skills that may underlie many aspects of community integration (e.g., adaptive behavior, executive function)

• Better understand the needs of adult service providers, as well as the characteristics of effective providers.

• Encourage more skilled workers to enter and remain in the adult disability service provider field, which is critical to improving self-determination of adults with ASD.

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Aspirational Goal: Develop, enhance, and support infrastructure and surveillance systems that advance the speed, efficacy, and dissemination of ASD research and services.

INTRODUCTION

Appropriate research infrastructure is critically important In 2010, the IACC decided to track investments and evaluate to the success of the IACC Strategic Plan, and progress progress in this area in the same organized, rigorous manner toward the Aspirational Goal has been rapid over the past that is used in the rest of its Strategic Plan. From 2009-2015, 8 years. New databases are being built to leverage recent a total of $302 million dollars has been invested in building genetics findings, and efforts to share biospecimens and maintaining ASD research infrastructure, including among multiple research efforts are intensifying. surveillance efforts. While many of the original infrastructure This increased availability of resources has advanced needs identified in 2010 have been accomplished, continued the efficacy and speed of ASD research. Surveillance investment is critical in order to maintain, develop, and systems have also progressed over the past 8 years, with build on these valuable resources. Specifically, there must new efforts focused on tracking more descriptive symptoms be a focus on enhancing the biorepository infrastructure, as well as a binary diagnosis. As the diagnosis of autism the data infrastructure, the human infrastructure, has broadened, more children are being identified who and surveillance activities in order for autism research do not have co-occurring cognitive disability, and to be successful. additional resources have been focused on serving the needs of people across a diverse spectrum. Furthermore, many government and private organizations regularly share lay-audience-friendly summaries of research findings to raise community awareness, including Simons Foundation, Autism Science Foundation, Autism Speaks, the Interactive Autism Network (IAN), the National Institutes of Health (NIH), and the Centers for Disease Control and Prevention (CDC).

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BIOREPOSITORY INFRASTRUCTURE

Biological materials repositories collect, process, store, and harvesting, storage, and tissue dissemination. Autism distribute biospecimens to support scientific investigation. BrainNet has a robust public awareness campaign to In the autism research community, biorepositories have encourage donation, led by the Autism Science Foundation, been developed to support collection and dissemination fulfilling one of the longstanding goals of the IACC Strategic of brain tissue, fibroblasts, and other tissues. Greater Plan. The NIH NeuroBioBank and Autism BrainNet work participation in brain and tissue banking is needed from closely together to ensure that tissue acquisition, processing, members of the autism community in order to obtain and distribution from both resources are conducted with enough samples to meet research requests. Outreach the highest standards possible. campaigns to encourage families to donate brain and other tissue need to be expanded and enhanced. TiSSUE BANKiNG

The NIMH Repository and Genomics Resource (NRGR) BRAiN BANKiNG provides a centralized national biorepository that plays The NIH NeuroBioBank was formed in 2013 to address a key role in facilitating ASD research. The repository the increasing demand for postmortem human brain tissue contains thousands of biospecimens from ASD families, for research purposes.1 Although this resource and accompanying genotypic and phenotypic data are provides tissues for wide-ranging neurological and available to qualified researchers worldwide. Biomaterials neurodevelopmental disorders, there is high demand are stored at the Rutgers University Cell and DNA Repository, for tissue from donors diagnosed with autism spectrum supported through a cooperative agreement from the disorders. The NIH NeuroBioBank supports six National Institute of Mental Health (NIMH). Clinical projects independent brain and tissue repositories; the University funded by NIMH that propose to collect biospecimens of Maryland site collects and distributes the majority of are strongly encouraged to submit the samples to NRGR. ASD tissue. The collection has been highly sampled over Submissions typically consist of whole blood draws along the years and continues to grow through outreach with the necessary phenotypic data relevant to these activities and collaborations with other organizations. samples. The NRGR also accepts plasma, DNA/RNA/ cDNA, biopsied material, and human-derived cell A more autism-focused effort was undertaken in 2015 by lines such as induced pluripotent stem cells (iPSCs) the Autism BrainNet, supported by the Simons Foundation. and lymphoblastoid cell lines (LCLs). Other types of Autism BrainNet is focused exclusively on creating a biospecimens (e.g., saliva) may be accepted on a case- collection of ASD and control brains. The program supports by-case basis. There are currently 18,822 ASD samples four nodes throughout the United States (New York, across all diagnoses of ASD in the NRGR Autism Massachusetts, Texas, and California) and one in the United distribution. Another 12,606 have been received and Kingdom that share standardized protocols for tissue will be released in future distributions.

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DATA INFRASTRUCTURE

Data infrastructure refers to data collection, storage, sharing, The National Database for Autism Research (NDAR) was and consumption to support autism research, services, implemented in 2008 to harmonize research data and share and policy development. Autism is a highly heterogeneous results for all human subject research studies, by supporting disorder requiring large sample sizes to make significant a de-identified research subject identifier – the NDAR findings. Thus far, tens of thousands of research subjects Global Unique Identifier (GUID), and a precise method have consented to make their genomics, imaging, and clinical for associating research data with publications/results.2 research data available to scientists in the hope that those NDAR also supports common data definitions, a data will help lead to important research discoveries. standardized set of data collection measures ensuring These datasets have become very large (i.e., millions of that results across studies can be accurately combined or gigabytes) and will likely grow exponentially in the coming compared. Initially implemented to support data sharing years with the rapid advances in technology (e.g., raw for the NIH Autism Centers of Excellence, NDAR was imaging, whole genome sequencing), new methods of data expanded to support data sharing of any autism research acquisition (bio-tracking), and the integration of patient- data funded by NIH extramural programs beginning in directed reporting applications (e.g., IAN and SPARK). 2010. In 2013, NDAR was rebranded as the NIMH Data Other research communities have established related data Archive (NDA) and now supports data sharing of all human repositories and funded data sharing initiatives making subject research data related to mental health. Today, those datasets broadly available for use by the autism research data from over 600 research projects, representing research community. Given the size of these data and the a public research investment of over $1.4 billion, are being complexity of the software, algorithms, and analytic methods shared. Overcoming limitations on restricted use datasets used, it is essential that all the data and associated or the sharing of human subject research data across metadata be shared when a result is published or a international borders, the NDA allows for the availability significant finding is announced. Ensuring that all data is of research data funded by Autism Speaks, the Simons shared will increase the rigor and reproducibility of findings, Foundation, and the Autism Science Foundation. Investment a core responsibility of publicly funded research. is still needed to extend this infrastructure to support big data analytics better and to integrate with biobanks DATA BANKS and genomics data repositories more fully.

New findings, technologies, and research methods have Another mechanism for data sharing is the Autism emerged that can drive autism research forward, capitalizing Sequencing Consortium (ASC), an international group of on advances in participant engagement through electronic scientists who share autism samples and genetic data.3 portals and the collection of large data sets. Together, Currently, ASC has whole exome sequencing (WES) these participant-powered and clinical data networks can data for 29,000 samples, many of which are derived from be further leveraged for rapid research on large numbers DNA samples in the NIMH repository. Summary data is of participants throughout the country, offering the potential available for all samples, as is raw and called data for for a broad and rich view of the health and well-being of those with ASD and their families.

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samples with appropriate consents. Permission to the information available on that participant is thereby re-contact research participants from completed studies enhanced. Care should be taken to ensure that all exists for many of the samples within the ASC, managed stakeholders across the research enterprise understand by the contributing site. the importance of data sharing and that those sharing the most used and highest quality datasets be credited for In 2016, the Simons Foundation launched SPARK (Simons their contributions. To facilitate data sharing in research Foundation Powering Autism Research for Knowledge) to involving human participants, an identifier or code is used recruit, engage and retain a cohort of 50,000 individuals to identify and link each individual to his or her specimens with ASD, as well as their family members, to participate and perhaps also to associated medical information; in autism research. To participate in SPARK, families enroll use of a de-identified code (i.e., a code that does not reveal online, provide saliva samples for genetic analysis, and the identity of the individual) maintains privacy of the agree to be re-contacted for future research opportunities. individual’s information. The GUID was developed to SPARK participants are being sequenced and genotyped provide an easy method of identifying the same research to identify new genes associated with autism risk. Clinical, participant across various data repositories and biobanks behavioral, and genetic data on the SPARK cohort are while maintaining the privacy of their personal information. available to all qualified investigators, and SPARK participants The advantage of the GUID is that it enables linkage of data can be invited to participate in other ASD research studies. and specimens for a given individual over multiple studies, Thus far, SPARK has enrolled over 48,000 individuals, which can enrich the data set and prevent unnecessarily including 19,000 individuals with ASD. repeating the collection of the same types of samples from a given individual for multiple studies. While most data In 2016, the Autism Science Foundation launched the repositories have standardized identification of research to collect and distribute DNA from Autism Sisters Project participants using the GUID, adoption of this method the unaffected female siblings of individuals with autism. has been less consistent across biobank repositories. Current research suggests that genes implicated in autism Compounding this problem is the fact that most of the are equally distributed in boys and girls, but that many girls biobanks hold samples that are consented for restricted use who carry the autism genes do not express clinical (e.g., a study of autism and schizophrenia would require symptoms of autism due to a “female protective effect.” separate access) and are shared in separate repositories The goal of this new project is to collect DNA samples with different access restrictions and policies. The result is to enable researchers to discover and characterize that it is often easier to request a tissue or sample from this “female protective effect.”4,5 a biobank, re-sequence or re-analyze it, and then share the data with a new and different identifier, causing unnecessary DATA SHARiNG (and often undetectable) duplication. For genomics, tools When all research projects share their data, the quality have been developed to eliminate this duplication, and of the accumulated data increases. For example, when a attempts have been made to provide similar safeguards new research participant is enrolled in a research study, for imaging data. Though these additional tools exist, it is that person may also have registered previously with one strongly encouraged that all data and biobank repositories or more data or biorepositories. If the data are linked maintain the use of the GUID and that those publishing and widely accessible to researchers (with appropriate genomics- or biobank-related studies provide a publicly privacy protections in place), the potential richness of available manifest of subject GUIDs and links to phenotypic

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data locations when publishing, even if the data are only Several national surveys and administrative efforts collect available as restricted use datasets. This action will provide information about people with ASD. Many of these surveys standardization allowing data from the same individual are Federally funded through agencies such as CDC to be linked across repositories, eliminate data duplication, [National Health Interview Survey (NHIS)], the Health and help minimize redundant sample and tissue requests, Resources and Services Administration (HRSA) thereby conserving precious resources. [National Survey of Children's Health (NSCH)], and the Department of Education [National Longitudinal Transition Supporting the increasing emphasis on the importance Study 2012 (NLTS 2012)]. Although each responsible of data sharing, NIH has established a two-tiered agency may focus on its own research priorities when approach for the sharing of NDA research data involving collecting and analyzing the data, synchronization of human subjects. First, observational and raw data is the national data sources will maximize their utility. to be defined and shared using established data standards Concordance of questions and sampling across surveys (data dictionary and a GUID). All data related to research and administrative data could add greatly to the results are expected to be submitted prior to publication. comparability of research undertaken across these national Data supporting other aims remain embargoed until platforms. Additionally, infrastructure for linking these publication, protecting ongoing research. This approach surveys to other sources of data is essential. The precedent directly follows the long-established research process of for linkage already exists: for example, the CDC links the sharing results and data at the time of publication. Where NHIS to administrative records from the Department of data collected by other researchers are used, this system Housing and Urban Development (HUD), which allows automatically provides a mechanism showing data for the addition of detailed housing information for those provenance and providing credit. All repositories supporting NHIS participants who use HUD services. Additionally, autism research should implement a similar program, even Federal Statistical Research Data Centers make national if the datasets shared are summary datasets, are not easily data from the Census bureau, CDC, and the Agency for harmonized with established data repositories, or have Healthcare Research and Quality (AHRQ) available restricted use limitations. As a community, by responsibly to researchers in one place. More projects like these, and sharing high quality data at the appropriate times, it will additional means of capitalizing on the data that has already increase the return on the collective research investment, been collected and funded, are a key priority in order to protect the intellectual contribution of the best scientists, generate an expansion of the information available on and help accelerate research discovery in autism and autism to a nationally representative sample. related disorders. Collectively, open data sharing offers the best opportunity to reach the sample sizes that are likely needed to improve understanding of autism and related disorders.

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HUMAN INFRASTRUCTURE

Human infrastructure refers to the development of While these initiatives represent mechanisms for the human resources necessary to support autism research. general support of trainees and early career ASD These include developing a professional workforce to conduct investigators, an area of need and opportunity identified by research and provide services, as well as encouraging the IACC is for these up-and-coming researchers to have individuals with autism and their family members to better access to existing datasets for conducting secondary participate in autism research. In addition, systems must data analysis. Hundreds of millions of Federal and private be developed to share research findings with community donor dollars have been spent on ASD research, which stakeholders and translate research findings into policy has led to the collection or federation of data on tens of and practice. thousands of ASD cases. A modest investment aimed at improving access to these data would not only maximize Individuals with autism and their families participate in the return on substantial financial and human capital research studies at relatively low rates, hampering the investments represented by decades of ASD research, ability of researchers to fully understand ASD and but would also provide a fast-tracked training mechanism develop interventions. Coordinated efforts are needed to ideally suited to early career investigators, who often educate stakeholders from diverse backgrounds on the lack the resources to collect primary data. importance of participating in research. Research should also be conducted to understand the barriers that discourage Workforce development is an area of immense need as participation. Efforts should also be made to encourage the number of identified individuals with autism continues families from diverse backgrounds to donate biological to grow. While progress has been made in the area of early samples for research. detection and intervention, and in the support of children on the spectrum, much less effort has been expended on RESEARCH TRAiNiNG AND WORKFORCE adult services, as tens of thousands of children with autism DEVELOPMENT EFFORTS transition to adulthood. Further, there is a dearth of trained medical professionals that are knowledgeable in There are a number of efforts underway to enhance research providing care to the autism community, particularly the training and workforce development. Private funding adult community. The Autism Collaboration, Accountability, agencies such as Autism Speaks and the Autism Science Research, Education, and Support Act, IDEA Part C, and Title V Foundation support research fellowships that focus on Maternal and Child Health Block Grants all provide some attracting and nurturing early career investigators as amount of Federal funding intended to target workforce they pursue innovative ASD research projects and begin training and development programs. However, resources their careers. Great emphasis is placed on building remain scarce, and it is not immediately clear how some relationships with experienced mentors and on encouraging of those resources are being utilized, particularly regarding multidisciplinary avenues of exploration. NIH also offers whether there is any standardization in the delivery of research training opportunities including, but not limited to, workforce development efforts across communities. training and career development grants and travel awards for In some cases, it is unclear what training programs are early career investigators to attend research conferences.

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being implemented, if they are evidence-based, and how DiSSEMiNATiON OF SCiENCE they are evaluated. There seems to be an immediate need for Increasing and improving mechanisms for dissemination evidence-based best-practice guidelines in the development of research findings after publication should be a priority and implementation of such training programs. for the autism community. It is vital that findings and iNTERNATiONAL COLLABORATiON data become more accessible to researchers, practitioners, families, and the general public. Training to improve A 2012 IACC report titled Autism Spectrum Disorder science communication skills should be more readily Research Publication Analysis: The Global Landscape of available to researchers who wish to share their work Autism Research highlighted the expanding web of ASD with lay audiences. Particularly important is risk research collaboration and publications across the globe; communication in the interpretation of research findings, researchers from over 50 countries published papers as the information disseminated to the public is sometimes during the analysis period. While there has been contradictory, oversimplified, overstated, or sensationalized. an increase in ASD research conducted and published This misinformation can confuse the risk, disenfranchising outside of the US and other developed countries, the members of the public, and have a negative impact report also called attention to the fact that while research on research participation. Mechanisms that allow for efforts are robust in the US, Canada, Europe, Australia, the summation of the evidence base into actionable and China, many other countries around the world are recommendations such as systematic reviews and lacking in capacity to conduct research or provide meta-analysis are encouraged, though research funders opportunities to participate in research. More attention often overlook the potential for these types of analyses and investment toward fostering international research because they are based on existing rather than new collaborations have the potential to change this situation data. Much of this work will be more feasible as the and provide benefits for people with autism and other data sharing infrastructure further develops and expands. developmental disabilities worldwide. Diverse settings can NDAR provides an infrastructure to make data broadly afford unique research opportunities to investigate risk accessible through a universal platform and federation factors (e.g., air pollution) and populations (e.g., higher with other data sources. To make NDAR the most useful genetic homogeneity) that may not be present in countries resource possible for the community, autism researchers from which most of ASD research is currently published. must improve both the consistency and quality of data Further, international research collaborations not only shared, especially those data supporting published present opportunities to disseminate and implement results, allowing the infrastructure to be better utilized evidence-based science and services in diverse settings and supporting the dissemination of scientific advances. around the world, but also allow the ASD research NDAR and similar data sharing efforts can help maximize community to learn about how diverse populations, the return on Federal and private investment in autism including those from low-resource settings, have addressed research made over the last decade by providing the issues such as limited research infrastructure and large research community with richer datasets and opportunities service gaps. For these reasons, it is imperative that for research that would not have been possible without international research efforts and collaborations continue the coordination of these data. to be promoted and supported. Technology can play a key role in improving the dissemination of science, and advances in technology have made it increasingly possible to handle the troves

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of “big data” that have been collected in ASD research. and implementation of intervention and support services, In addition to combining, storing, and analyzing data, via telehealth or e-learning, is critically important to technology affords new avenues of information collection improving the capacity to deliver the latest in evidence-based and dissemination, for example, in the form of mobile services throughout the US and around the world. Lastly, applications (apps). Researchers can better collect data with growing awareness of ASD around the world and an and do so more consistently across research studies by increase in the number of local organizations supporting utilizing technology-based research platforms. Similarly, people with ASD in their communities, it is an opportune practitioners can better collect clinical data using the same time to begin building stronger international collaborative or similar platforms. Making this technology more accessible efforts around ASD. Such initiatives have the potential and promoting the development of new technology for to enhance communication and cooperation between data collection and sharing should be prioritized by governments, researchers, service providers, and advocates the research community to help optimize autism research and to aid in dissemination of research findings and best studies. Further, technology to promote dissemination practices globally.

SURVEILLANCE

Population-based surveillance for autism spectrum are collected for other purposes and do not always contain disorder is essential for monitoring time trends in prevalence, adequate and pertinent information. Health surveys are assessing patterns by demographic factors and level of nationally representative, generate data relatively quickly, support necessary, characterizing co-occurring conditions, include extensive questions on service needs and estimating resource needs, and stimulating research into utilization, include a comprehensive age range of children, potential risk factors. For the data provided to be used and are cost-effective in terms of the marginal cost effectively, surveillance should be as complete and valid as of adding ASD-related questions; however, the validity of possible. Population-based studies of the prevalence and parent/caregiver-reported ASD has not been established, characteristics of autism spectrum disorder in the United and declining response rates have raised concerns about States have been conducted among children, but continued bias. Expert review of records from multiple sources, collection is necessary to monitor trends. In addition, there including healthcare and education records, can ascertain is a pressing need for surveillance studies among adults. records-based data on a number of factors such as demographics, educational placement, intellectual and There are several different methodologies currently used adaptive function, and behavioral phenotype. However, this for estimating the prevalence and characteristics of autism methodology is dependent on data in children’s records, spectrum disorder among children, including: 1) use of focuses on a few specific ages, and is resource- and administrative records; 2) parent or caregiver surveys; time-intensive and so currently cannot be done at a 3) expert review of records from multiple sources; and national level. Finally, screening and examination of children 4) screening and examination of children. Each of these using a standardized and validated ASD diagnostic tool is methodologies has strengths and limitations. Administrative a rigorous methodology that attempts to give all children records are readily available and cost-effective to use, but

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in the selected population an opportunity for ascertainment. and the potential high cost of initial screening. Nevertheless, However, this methodology is also resource- and time- a comprehensive adult surveillance in the United States intensive and cannot currently be done on a national level. would be desirable, subject to available funding. In addition, low response rates in previous studies suggest a potential for bias. CURRENT SURVEiLLANCE PROGRAMS Autism and Developmental Disabilities Continued ASD surveillance among children is essential to Monitoring Network monitor prevalence trends (including disparities in prevalence by demographic factors), characterize co-occurring The Autism and Developmental Disabilities Monitoring conditions, estimate resource needs, and stimulate research (ADDM) Network is a population-based surveillance into potential risk factors. ASD surveillance systems program for ASD and other developmental disabilities based should be complementary, offering unique strengths and on expert review of behavioral characteristics documented contributions that will further the understanding of the in developmental evaluations contained in children’s population of individuals with ASD. Where appropriate, healthcare and educational records. CDC has been data collection should be designed to allow comparisons conducting surveillance for ASD among 8-year-old children across systems. Linkage of surveillance data with other state through the ADDM Network every 2 years since 2000 and Federal datasets should be encouraged to leverage at between six and 14 sites throughout the United States. the surveillance efforts and expand the scope and utility Recent surveillance cohorts have included approximately of the information collected. 350,000 8-year-old children. In 2010, the ADDM Network was expanded to include surveillance for ASD among While many research studies are focused on understanding 4-year-old children in six sites of the ADDM Network. Data and meeting the needs of children with ASD, much less have been linked to various sources such as environmental effort has been expended on adults. There is an urgent pollutant monitoring, juvenile justice records, and others. need to expand ASD surveillance to adults to characterize Additional linkages to data from state and Federal agencies prevalence, adolescent/young adult transition needs, would enhance the usefulness of the ADDM Network employment and housing, co-occurring conditions, data. The ADDM Network methodology has remained premature mortality, and other lifespan issues. In particular, stable over time and so is able to assess prevalence trends. investigating ASD prevalence in adults will help researchers The most recent prevalence estimate for 2012 was 14.6 understand how the interaction of ASD and co-occurring per 1,000 8-year-old children.8 The ADDM Network conditions impacts the ability to adults with ASD to live methodology also allows for assessment of the effect of and work. changes in diagnostic criteria for ASD, and an evaluation of the effect on ASD prevalence and characteristics of A systematic community survey in the United Kingdom the change from DSM-IV-TR to DSM-5 is underway. estimated that approximately 1% of adults surveyed met 6,7 the criteria for ASD, a rate similar to that in children. National Survey of Children’s Health None of the adults with ASD identified in this study had been previously screened or diagnosed, further confirming The National Survey of Children’s Health (NSCH) is cur- the need for ASD surveillance in adults. The researchers rently administered by the Maternal and Child Bureau of involved in the study noted several challenges to their HRSA. This nationally representative telephone survey methodology, including low response rates to the survey

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of children’s health and development based on parent/ variety of topics including the child’s health status, healthcare caregiver report includes questions on whether the child access and utilization, and a mental health screener currently had an ASD as well as whether a healthcare (the Strengths and Difficulties Questionnaire), as well as provider ever informed the parent or caregiver that the family factors, including sociodemographic factors. ASD child had an ASD. Data are also collected on a variety of prevalence was 2.24% for children aged 3-17 years in topics including the child’s health, health as an infant, 2014. The questions that establish a child’s ASD status recent healthcare service, experiences with healthcare were recently revised to be the same as those in the providers, health insurance coverage, sociodemographic NSCH. As with NSCH, linkages to data from other Federal factors, and the child’s learning, home, and family agencies should be encouraged to expand the scope and environment. The most recently published report usefulness of the data. presented data for over 90,000 children aged 6-17 years; ASD prevalence was 2.00% for children aged 6-17 years South Carolina SUCCESS in 2011/2012. Beginning in 2016, this survey was moved The South Carolina Children’s Educational Surveillance to a mail-invitation, online survey based on a US Census Study (SUCCESS) is an Autism Speaks-funded Bureau sampling platform. This survey has been combined screening-based initiative designed to help improve the with the previously fielded National Survey of Children precision of US ASD prevalence estimates by reducing with Special Healthcare Needs. The new combined survey reliance on service records alone to make ASD diagnoses, will be conducted every year and include approximately addressing the chief limitation of the ADDM Network 100,000 children aged 0-17 years. It is anticipated that approach. It has been suggested that this methodological state-level estimates will be available for many variables, approach is subject to missed cases, particularly among and for other variables data will be combined from several populations with less access to services, and in sites with study years to provide state-level estimates. Linkages to fewer record types. SUCCESS was designed as a replication data from other Federal agencies should be encouraged to of the first-ever total population study of ASD prevalence expand the scope and usefulness of the data collected. in South Korea which found 2.64% of 7-9 year-old children, or 1 in 38, had an ASD.9 SUCCESS similarly implements National Health Interview Study a direct-screening protocol of all eligible school children CDC conducts the National Health Interview Survey in the catchment area, to both augment and compare (NHIS), a nationally representative survey of parents/care- to the records-based case ascertainment methodology givers that provides data on the health of children in of the South Carolina ADDM Network site. In addition to the United States, including information on whether a improving the estimation of the prevalence of ASD within healthcare provider ever informed the parent or caregiver a US site, SUCCESS intends to characterize the factors that the child had an ASD. The US Census Bureau is the contributing to why cases may be missed using current best data collection agent and the data are collected through surveillance practices. It is also the first study to compare personal household interviews. Data are collected on DSM-IV and DSM-5 prevalence using a population-based children aged 0-17 years every year; the most recently methodology in the US. The findings, currently in published survey year, 2014, presented data on ASD preparation, will better guide ASD surveillance practices prevalence and characteristics for approximately 13,000 in the US, including resource and infrastructure needs, children aged 3-17 years. Data are also gathered on a moving forward.

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SUMMARY

Continuing to build the infrastructure necessary for autism make significant contributions to our understanding of research is an important priority. In particular, researchers ASD. Inclusion of people on the autism spectrum and their must make efforts to standardize their data collection and families in research planning is also important, as it will help share with others in order to build higher-powered studies ensure that studies maintain a focus on issues that matter across multiple areas of research. Research institutions most to those who are impacted by ASD. Finally, funding must continue to support biobanks and databanks, and agencies should continue to devote resources to ensuring to work towards integrating common collection and dissemination of research findings and best practices, processing methods. Efforts to increase the participation gaining better understanding of ASD prevalence across of individuals with autism and their families in research the lifespan, and training the next generation autism and contributions to biorepositories are important, as researchers, clinicians, and care providers. information and samples gathered have the potential to

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OBJECTIVES

OBJECTiVE 1: Promote growth, integration, and coordination of biorepository infrastructure.

Examples:

• Promote biological sample donation to ensure that demand for research studies is met.

• Develop and expand programs and outreach campaigns to encourage families from diverse backgrounds to participate in ASD research, join registries, and donate biological samples.

• Create incentives to encourage standardization and sample sharing across data and biorepository banks.

OBJECTiVE 2: Develop, enhance, and link data repositories.

Examples:

• Adopt a de-identified research participant/subject identifier, such as the GUID, across all research initiatives in order to reduce the likelihood of sample duplication.

• Use common data definitions in order to standardize data collection, and responsibly share all the data supporting any findings when those findings are announced.

OBJECTiVE 3: Expand and enhance the research and services workforce, and accelerate the pipeline from research to practice.

Examples:

• Expand and enhance programs that provide funds to train current and future researchers on innovative research techniques.

• Provide service providers with training in evidence-based ASD services across multiple settings from clinics to communities.

• Develop programs to translate and disseminate ASD research findings into actionable recommendations and real-world practice.

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OBJECTiVE 4: Strengthen ASD surveillance systems to further understanding of the population of individuals with ASD, while allowing comparisons and linkages across systems as much as possible.

Examples:

• Expand surveillance efforts to include the adult population in order to gain a better understanding of needs and concerns over the lifespan.

• Expand surveillance efforts to collect more descriptive data regarding co-occurring conditions, including cognitive disability, seizure disorders, anxiety, and depression to increase understanding of the prevalence of these conditions in the ASD population.

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BUDGET RECOMMENDATION

In the preceding chapters, the Interagency Autism Coordinating Committee (IACC) has provided information about recent research progress and services activities as well as 23 new strategic objectives to guide future efforts to better understand and address the needs of people on the autism spectrum across the lifespan and all levels of ability and disability. Under the Autism CARES Act, the IACC is also required to include “proposed budgetary requirements” in the Strategic Plan. The following information provides supporting background information and the IACC budget recommendation for the 2016-2017 Strategic Plan for Autism Spectrum Disorder (ASD).

ASD is a lifelong condition, and as such, it results in significant human costs across the lifespan, not only in healthcare and services costs, but also in lost economic productivity, and reduced individual quality of life. These true costs reflecting lost human potential have recently begun to be described by thorough analyses. One of the most notable studies to date has estimated that the total lifetime cost (including spending and lost productivity) for supporting a person with ASD in the United States averages $2.4 million for ASD with intellectual disability, and $1.4 million for ASD without intellectual disability.1 Another study estimated that the additional costs of healthcare, education, therapy, services, and caregiver time associated with caring for a child with ASD aged 3 to 17 years is about $17,000 per year.2

The total annual cost of ASD in the United States – including medical, non-medical, economic, and lifetime costs, among others – has been estimated to be at least $236 billion. Of the estimated $236 billion, the cost of supporting children with ASD was at least $61 billion per year, and the annual cost for adults with ASD was at least $175 billion.1 Another study has suggested that in 2015 the combined medical, non-medical, and lost productivity costs were in the range of $162-$367 billion, or 0.89-2.0% of the US gross domestic product.3 By contrast, the Interagency Autism Coordinating Committee (IACC) portfolio analysis data from 2015 indicates that combined autism research funding among Federal and private sources totaled $343 million – only 0.09-0.21% of the estimated total annual cost of ASD.

While it is evident that more work needs to be done to fully understand the impacts of ASD on our society, there are several ways in which investment in research may be able to effect long-term benefits to individuals and society, as well as cost savings. Research on the biological basis of ASD may lead to the identification of modifiable risk factors that could reduce disability associated with ASD, as well as enable earlier diagnosis and improved interventions. There is already evidence that the costs of research and services that enable delivery of effective early intensive behavioral interventions in childhood can result in cost savings over the lifespan by reducing the need for costly long-term care and support.4,5 A recent study found that the health-related costs of the Early Start Denver Model were fully recouped after only a few years because children receiving the intervention required fewer other services, such as applied behavior analysis.6 In addition, we know that an estimated four out of ten young adults with autism do not transition to a job within the first years after completing high school, and those who do find work are often relegated to part-time or low-wage jobs.7 It is therefore also likely that more investment in research to improve adolescent and adult services and supports would improve the economic productivity of individuals over their entire lifetime, while also improving their sense of purpose and quality of life.8

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Although there was significant growth in autism research funding from 2008 to 2010, and additional Federal funding from the American Recovery and Reinvestment Act (ARRA) provided a welcome boost in 2009 and 2010, ASD research funding levels have since become relatively flat. The loss in momentum has been accelerated by the loss of purchasing power over time due to inflation, resulting in what was effectively 15% of funding that was lost to inflation in 2015 alone (Figure 1). At the same time, never before have there been such promising scientific advances in ASD research, as well as a recognition of the full range of ASD research that will require attention and resources in order to truly improve the lives of individuals across the autism spectrum and lifespan. In the 2016-2017 IACC Strategic Plan, the IACC has identified 23 new strategic objectives that represent areas of significant opportunity in the autism field and with enhanced funding have the potential to address critical needs of the autism community.

With these goals in mind, the IACC considered historical ASD funding trends and projected the budgets that will be nec- essary to propel ASD research forward and ensure there is meaningful progress on the priorities identified in this newly updated IACC Strategic Plan. Given the tremendous needs of the autism community as well as the promising opportunities for research and services that have been outlined in this Strategic Plan, the IACC recommends doubling the 2015 combined Federal and private autism research budget level of $343 million to $685 million by the year 2020. To accomplish this goal with steady and predictable annual funding increases, a roughly 14.85% increase in the autism research budget would be required each year (Figure 2). It is important to point out that this budget recommendation applies to ASD research budgets only; an IACC analysis of services budgets will be forthcoming in future years. Furthermore, the research funding increases recommended by the IACC would not be sufficient to accomplish all of the research goals identified in this Plan. However, a specific effort to double the autism research budget in 5 years would represent an aggressive, yet realistic jump-start to support research that can significantly move the field forward.

As evidenced by the analysis of the autism research portfolio from 2008 to 2015, an infusion of resources would be wisely and efficiently leveraged, with many areas of autism research well-poised to capitalize on additional investment. While all areas of the autism research portfolio require increases in funding, the areas identified by the IACC that are in particular need of resource growth include:

1. Research to support development and delivery of new and improved treatments and interventions

2. Research to enable development and delivery of evidence-based services

3. Research on lifespan issues, especially to understand and address the needs of transition-age youth, young adults, and older adults on the autism spectrum.

In addition, the investment of resources targeting these areas would serve not only to incentivize research on these topics, but also to encourage additional well-trained scientists to specialize in these research areas of significant need.

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THE OVERALL ASD RESEARCH BUDGET HAS PLATEAUED AND LOST PURCHASING POWER FROM 2008-2015

Overall ASD Funding – in actual dollars

Overall ASD Funding (without ARRA) – in actual dollars

Overall ASD Funding – in 2008 constant dollars

Overall ASD Funding (without ARRA) – in 2008 constant dollars

$450

$408.6M

$400

$342.6M $350 Millions $291.9M $300

$250 $222.2M

$200 2008 2009 2010 2011 2012 2013 2014 2015

Figure 1. The history of combined Federal and private autism research funding from 2008 to 2015 in actual (blue) dollars and 2008 constant (orange) dollars shows that after experiencing an initial increase, the ASD research budget became relatively flat and lost purchasing power due to inflation in recent years. The dotted lines indicate funding levels excluding American Recovery and Reinvestment Act (ARRA) stimulus funds, which provided supplementary funding in 2009 and 2010. Inflation effects were calculated using the Biomedical Research and Development Price Index (BRDPI).9

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THE IACC RECOMMENDS DOUBLING THE ASD RESEARCH BUDGET BY 2020

$800

$685 $700

$596

$600 $519

$500 $452

$394

$400 $343 Millions

$300

$200

$100

$0 2015 2016 2017 2018 2019 2020

Figure 2. The IACC believes doubling the combined Federal and private ASD research budget to $685 million would spark progress on the 23 new Strategic Plan objectives. A steady and predictable path to doubling the 2015 ASD research budget by the year 2020 would require an overall budget increase of about 14.85% each year.

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STATEMENT ON DUPLICATION OF EFFORT

The Autism CARES Act requires the IACC in its Strategic Plan to provide “Recommendations to ensure that autism spectrum disorder research, services and support activities, to the extent practicable, of the Department of Health and Human Services and of other Federal departments and agencies, are not unnecessarily duplicative.”

The 2016-2017 IACC Strategic Plan for ASD offers wide-ranging objectives that are designed to address gaps in ASD research, services, and support activities. The IACC’s intention is that each broad-based objective will be accomplished through multiple projects addressing various aspects of these complex issues, which will be funded by multiple agencies in a coordinated fashion. The IACC is charged with ensuring that coordination, which is achieved by fostering dialogue among Federal agencies and private organizations and engaging their input in the development of plan objectives. The IACC believes that in the case of scientific research, coordinated efforts by multiple public and private agencies to fund different types of projects within the same objective represents cooperation and collaboration, not duplication. In addition, the scientific process requires that studies be independently replicated in order to ensure reproducibility and validate findings. Replication of an experiment or approaching a single problem using different methods can corroborate findings and help researchers distinguish between false leads and important discoveries. Replication also contributes to efficiency in research funding by ensuring the creation of a solid base of validated findings that establish the rationale for later-stage, larger, and potentially more costly research efforts. For these important reasons, replication of research is valuable and should not be considered duplication of effort.

In 2013, the US Government Accountability Office (GAO) released a report entitled Federal Autism Activities: Better Data and More Coordination Needed to Help Avoid the Potential for Unnecessary Duplication (GAO-14-16). The GAO report suggested that the IACC should more fully take advantage of research project data collected to identify opportunities to enhance coordination and prevent duplication. The Autism CARES Act provided more specificity in requiring the IACC to make recommendations about ways in which duplication could be avoided in its Strategic Plan. In the process of preparing this Strategic Plan, the IACC reviewed funded research projects to monitor the extent to which strategic objectives are being accomplished, including changes in funding over time. The IACC explicitly asked each of the seven working groups assisting with preparation of content for the Strategic Plan to identify issues related to duplication and to propose suggestions for avoiding unnecessary duplication.

The IACC did not find any specific instances of duplication among projects in the 2013 portfolio of funded autism research projects, but it noted that there are several instances of the opposite of duplication within the portfolio – gaps in research where too few projects are being supported to answer key questions in the field. Examples include the lifespan area in Question 6, which has received relatively little funding over the years that the Strategic Plan has been in place, resulting in gaps in knowledge about the needs of youth and adults on the autism spectrum and research to develop innovative services and supports.

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The Committee also identified a broader issue that provides an opportunity to reduce duplication - the need for closer coordination of large genomic sequencing efforts. Several different research organizations are building genetic databases, and there is concern that different databases may be sequencing the same individuals, which could result in poor stew- ardship of funds as well as the time and effort of research participants. To reduce duplication of effort in sequencing, the IACC encourages organizations building databases to publicly share their “manifests” which include information on whose DNA is in each database, to use global unique identifiers (GUIDs) to tag data in order to help researchers know when they are working with an individual who already has been sequenced, and to share data by federating with or contributing to the National Database for Autism Research. As technology advances, there may be instances where resequencing the same individual is necessary to expand coverage or gather additional data that were not gathered previously. Ideally, in an environment where data sharing is maximized, researchers will be able to be more efficient with genomics research funding and participation of subjects in research so as to reduce duplication of effort.

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CONCLUSION

Much progress has been made in the autism field since the launch of the first IACC Strategic Plan in 2009. At that time, researchers and other professionals in the field were starting to explore and push toward the possibility of earlier diagnosis and intervention, to understand whether genetics or the environment play a larger role in etiology, to determine why autism was becoming a more common diagnosis, and to understand what were the major challenges of autism in adulthood. Since then, through research and service work in the community, we have learned that: children at risk for ASD can be identified as early as the first year; early intervention does lead to improved outcomes for many children; myriad genetic and environmental factors interact closely resulting in the observed heterogeneity of ASD; multiple factors may be influencing prevalence estimates and more children with milder forms of ASD are being detected; and there are tremendous unmet service needs for adults on the autism spectrum. While research and services activities have moved the field forward in many ways, as represented in the aforementioned examples, they have also brought to light many challenges that still need to be addressed.

Before developing the 2016-2017 IACC Strategic Plan for ASD, the IACC reviewed research progress and analyses of recent data describing the portfolio of ASD research funding in order to assess trends in funding and determine potential areas of opportunity. Overall funding for the autism research portfolio increased, from $222 million in 2008 to $343 million in 2015. Over the years the Committee has monitored the research portfolio, it has not identified any concerns about unnecessary duplication of effort across the portfolio, but it has monitored gaps and used this information to inform the development of the 2016-2017 IACC Strategic Plan.

Strategic investments in the autism portfolio have produced promising scientific advances over recent years. For example, since the last Strategic Plan Update in 2013, research findings have provided several new insights, such as a better picture of existing autism services and service needs, improved identification of genetic risk factors for ASD, and a more accurate representation of the broader ASD community – including girls and women, individuals with intellectual and language disabilities, adolescents, and aging adults. This new knowledge has further illuminated several areas ripe for future efforts and investments – investments that have the potential to improve quality of life while also producing long-term cost savings for individuals, families, and society. The 23 new objectives in this Strategic Plan describe priorities for autism research, services, and supports that reflect the most important opportunities and needs in the current autism landscape. Included in these objectives are a focus on detecting autism earlier and improving access to early intervention; advancing under- standing of the biology of autism and co-occurring conditions across the lifespan; integrating genetic and environmental information to understand autism risk; developing a wide array of new treatments and interventions that will address needs across the spectrum and across the lifespan; implementing interventions in community settings and improving access to services; improving transition services and quality of life for adolescents and adults; and enabling data sharing and expanded surveillance.

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The IACC continues to coordinate autism research efforts and reaffirms its commitment to our core values: responding with urgency to the needs and challenges presented by ASD, pursuing excellence in research, building a spirit of collaboration, remaining focused on the needs of the community, developing strategic partnerships, and striving for equity. As the IACC looks to the future and considers the outlook for its strategic goals, the Committee believes the autism field is poised to experience significant progress toward addressing the critical needs of the autism community in the coming years.

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QUESTiON 2: WHAT iS THE BiOLOGY UNDERLYiNG ASD?

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QUESTiON 3: WHAT CAUSES ASD, AND CAN DiSABLiNG ASPECTS OF ASD BE PREVENTED OR PREEMPTED?

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QUESTiON 4: WHiCH TREATMENTS AND iNTERVENTiONS WiLL HELP?

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76. Suzuki K, Sugihara G, Ouchi Y, Nakamura K, 82. Sun J, Allison J, McLaughlin C, Sledge L, Waters-Pick Futatsubashi M, Takebayashi K, Yoshihara Y, Omata B, Wease S, Kurtzberg J. Differences in quality between K, Matsumoto K, Tsuchiya KJ, Iwata Y, Tsujii M, privately and publicly banked umbilical cord blood Sugiyama T, Mori N. Microglial activation in young units: a pilot study of autologous cord blood infusion adults with autism spectrum disorder. JAMA Psychiatry. in children with acquired neurologic disorders. 2013;70(1):49-58. [PMID: 23404112] Transfusion. 2010;50(9):1980-7. [PMID: 20546200]

77. Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi 83. Cotten CM, Murtha AP, Goldberg RN, Grotegut CA, K, Buckwalter J, Courchesne E, Everall IP. Microglial Smith PB, Goldstein RF, Fisher KA, Gustafson KE, activation and increased microglial density observed Waters-Pick B, Swamy GK, Rattray B, Tan S, Kurtzberg in the dorsolateral prefrontal cortex in autism. Biol J. Feasibility of autologous cord blood cells for infants Psychiatry. 2010;68(4):368-76. [PMID: 20674603] with hypoxic-ischemic encephalopathy. J Pediatr. 2014;164(5):973-9 e1. [PMID: 24388332] 78. Bachstetter AD, Pabon MM, Cole MJ, Hudson CE, Sanberg PR, Willing AE, Bickford PC, Gemma C. 84. Sun JM, Grant GA, McLaughlin C, Allison J, Fitzgerald Peripheral injection of human umbilical cord blood A, Waters-Pick B, Kurtzberg J. Repeated autologous stimulates neurogenesis in the aged rat brain. BMC umbilical cord blood infusions are feasible and had no Neurosci. 2008;9:22. [PMID: 18275610] acute safety issues in young babies with congenital hydrocephalus. Pediatr Res. [PMID: 26331765] 79. Shahaduzzaman M, Golden JE, Green S, Gronda AE, Adrien E, Ahmed A, Sanberg PR, Bickford PC, Gemma 85. Dawson G, Sun JM, Davlantis KS, Murias M, Franz C, Willing AE. A single administration of human L, Troy J, Simmons R, Sabatos-DeVito M, Durham umbilical cord blood T cells produces long-lasting R, Kurtzberg J. Autologous Cord Blood Infusions effects in the aging hippocampus. Age (Dordr). Are Safe and Feasible in Young Children with Autism 2013;35(6):2071-87. [PMID: 23263793] Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Transl Med. 80. Ha S, Park H, Mahmood U, Ra JC, Suh YH, Chang 2017;6(5):1332-9. [PMID: 28378499] KA. Human adipose-derived stem cells ameliorate repetitive behavior, social deficit and anxiety in a 86. Sztainberg Y, Zoghbi HY. Lessons learned from VPA-induced autism mouse model. Behav Brain Res. studying syndromic autism spectrum disorders. 2017;317:479-84. [PMID: 27717813] Nat Neurosci. 2016 Oct 26;19(11):1408-1417. [PMID: 27786181] 81. Segal-Gavish H, Karvat G, Barak N, Barzilay R, Ganz J, Edry L, Aharony I, Offen D, Kimchi T. Mesenchymal 87. Katz DM, Bird A, Coenraads M, Gray SJ, Menon DU, Stem Cell Transplantation Promotes Neurogenesis and Philpot BD, Tarquinio DC. Rett Syndrome: Crossing Ameliorates Autism Related Behaviors in BTBR Mice. the Threshold to Clinical Translation. Trends Neurosci. Autism Res. 2016;9(1):17-32. [PMID: 26257137] 2016;39(2):100-13. [PMID: 26830113]

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88. Katz DM, Menniti FS, Mather RJ. N-Methyl-D- 94. French JA, Lawson JA, Yapici Z, Ikeda H, Polster Aspartate Receptors, Ketamine, and Rett Syndrome: T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Something Special on the Road to Treatments? Biol Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN. Psychiatry. 2016;79(9):710-2. [PMID: 27079494] Adjunctive everolimus therapy for treatment- resistant focal-onset seizures associated with 89. Khwaja OS, Ho E, Barnes KV, O'Leary HM, Pereira tuberous sclerosis (EXIST-3): a phase 3, randomised, LM, Finkelstein Y, Nelson CA, 3rd, Vogel-Farley V, double-blind, placebo-controlled study. Lancet. DeGregorio G, Holm IA, Khatwa U, Kapur K, 2016;388(10056):2153-63. [PMID: 27613521] Alexander ME, Finnegan DM, Cantwell NG, Walco AC, Rappaport L, Gregas M, Fichorova RN, 95. Grynszpan O, Weiss PL, Perez-Diaz F, Gal E. Shannon MW, Sur M, Kaufmann WE. Safety, Innovative technology-based interventions for autism pharmacokinetics, and preliminary assessment of spectrum disorders: a meta-analysis. Autism. 2014 efficacy of mecasermin (recombinant human IGF-1) May;18(4):346-61. [PMID: 24092843] for the treatment of Rett syndrome. Proc Natl Acad Sci U S A. 2014;111(12):4596-601. [PMID: 24623853] 96. Begum M, Serna RW, Kontak D, Allspaw J, Kuczynski J, Yanco HA, Suarez J. Measuring the 90. Buchovecky CM, Turley SD, Brown HM, Kyle SM, Efficacy of Robots in Autism Therapy: How McDonald JG, Liu B, Pieper AA, Huang W, Katz DM, Informative are Standard HRI Metrics. Proceedings Russell DW, Shendure J, Justice MJ. A suppressor of the Tenth Annual ACM/IEEE International screen in Mecp2 mutant mice implicates Conference on Human-Robot Interaction; Portland, cholesterol metabolism in Rett syndrome. Nat Oregon, USA. 2696480: ACM; 2015. p. 335-42. Genet. 2013;45(9):1013-20. [PMID: 23892605] https://doi.org/10.1145/2696454.2696480

91. Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont 97. Diehl JJ, Crowell CR, Villano M, Wier K, Tang K, Riek S, Charles P, Visootsak J, Brinkman M, Rerat K, LD. Clinical Applications of Robots in Autism Spectrum Koumaras B, Zhu L, Barth GM, Jaecklin T, Apostol G, Disorder Diagnosis and Treatment. In: Comprehensive von Raison F. Mavoglurant in fragile X syndrome: Guide to Autism. Patel VB, Preedy VR, Martin CR, Results of two randomized, double-blind, placebo- editors. New York, NY: Springer New York; 2014. controlled trials. Sci Transl Med. 2016;8(321):321ra5. p. 411-22. https://dx.doi.org/10.1007/978-1-4614- [PMID: 26764156] 4788-7_14

92. Ligsay A, Hagerman RJ. Review of targeted treat- 98. Kim ES, Paul R, Shic F, Scassellati B. Bridging the ments in fragile X syndrome. Intractable Rare Dis Res. Research Gap: Making HRI Useful to Individuals 2016;5(3):158-67. [PMID: 27672538] with Autism. Journal of Human-Robot Interaction. 2012;1(1):26-54. http://humanrobotinteraction.org/ 93. Wu JY, Peters JM, Goyal M, Krueger D, Sahin M, journal/index.php/HRI/article/view/25 Northrup H, Au KS, Cutter G, Bebin EM. Clinical Electroencephalographic Biomarker for Impending Epilepsy in Asymptomatic Tuberous Sclerosis Complex Infants. Pediatr Neurol. 2016;54:29-34. [PMID: 26498039]

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99. Brugha TS, Doos L, Tempier A, Einfeld S, Howlin P. 104. Grzadzinski R, Carr T, Colombi C, McGuire K, Outcome measures in intervention trials for adults Dufek S, Pickles A, Lord C. Measuring Changes in with autism spectrum disorders; a systematic review Social Communication Behaviors: Preliminary of assessments of core autism features and associated Development of the Brief Observation of Social emotional and behavioural problems. Int J Methods Communication Change (BOSCC). J Autism Dev Psychiatr Res. 2015 Jun;24(2):99-115. Disord. 2016 Jul;46(7):2464-79. [PMID: 27062034] [PMID: 26077193] 105. Parker KJ, Oztan O, Libove RA, Sumiyoshi RD, 100. McConachie H, Parr JR, Glod M, Hanratty J, Livingstone Jackson LP, Karhson DS, Summers JE, Hinman KE, N, Oono IP, Robalino S, Baird G, Beresford B, Charman T, Motonaga KS, Phillips JM, Carson DS, Garner JP, Garland D, Green J, Gringras P, Jones G, Law J, Hardan AY. Intranasal oxytocin treatment for social Le Couteur AS, Macdonald G, McColl EM, Morris C, deficits and biomarkers of response in children with Rodgers J, Simonoff E, Terwee CB, Williams K. autism. Proc Natl Acad Sci U S A. 2017;114(30): Systematic review of tools to measure outcomes 8119-24. [PMID: 28696286] for young children with autism spectrum disorder. Health Technol Assess. 2015 Jun;19(41):1-506. 106. Dawson G, Bernier R, Ring RH. Social attention: a [PMID: 26065374] possible early indicator of efficacy in autism clinical trials. J Neurodev Disord. 2012 May 17;4(1):11. 101. Ashwood KL, Buitelaar J, Murphy D, Spooren W, [PMID: 22958480] Charman T. European clinical network: autism spectrum disorder assessments and patient 107. Jeste SS, Frohlich J, Loo SK. Electrophysiological characterisation. Eur Child Adolesc Psychiatry. biomarkers of diagnosis and outcome in neuro- 2015 Aug;24(8):985-95. [PMID: 25471824] developmental disorders. Curr Opin Neurol. 2015 Apr;28(2):110-6. [PMID: 25710286] 102. Payakachat N, Tilford JM, Kovacs E, Kuhlthau K. Autism spectrum disorders: a review of measures for 108. Philip RC, Dauvermann MR, Whalley HC, Baynham clinical, health services and cost-effectiveness K, Lawrie SM, Stanfield AC. A systematic review and applications. Expert Rev Pharmacoecon Outcomes Res. meta-analysis of the fMRI investigation of autism 2012 Aug;12(4):485-503. [PMID: 22971035] spectrum disorders. Neurosci Biobehav Rev. 2012 Feb;36(2):901-42. [PMID: 22101112] 103. Esler AN, Bal VH, Guthrie W, Wetherby A, Ellis Weismer S, Lord C. The Autism Diagnostic Observation 109. Rane P, Cochran D, Hodge SM, Haselgrove C, Schedule, Toddler Module: Standardized Severity Kennedy DN, Frazier JA. Connectivity in Autism: Scores. J Autism Dev Disord. 2015 Sep;45(9):2704- A Review of MRI Connectivity Studies. Harv Rev 20. [PMID: 25832801] Psychiatry. 2015 Jul-Aug;23(4):223-44. [PMID: 26146755]

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110. Stavropoulos KK-M. Using neuroscience as an 113. Nicolaidis C, Raymaker D, McDonald K, Dern S, outcome measure for behavioral interventions in Ashkenazy E, Boisclair C, Robertson S, Baggs A. Autism spectrum disorders (ASD): A review. Collaboration strategies in nontraditional Research in Autism Spectrum Disorders. 2017;35: community-based participatory research partnerships: 62-73. https://doi.org/10.1016/j.rasd.2017.01.001 lessons from an academic−community partnership with autistic self-advocates. Prog Community 111. Calderoni S, Billeci L, Narzisi A, Brambilla P, Retico Health Partnersh. 2011 Summer;5(2):143-50. A, Muratori F. Rehabilitative Interventions and [PMID: 21623016] Brain Plasticity in Autism Spectrum Disorders: Focus on MRI-Based Studies. Front Neurosci. 2016 Mar 31;10:139. [PMID: 27065795]

112. Adams ZW, McClure EA, Gray KM, Danielson CK, Treiber FA, Ruggiero KJ. Mobile devices for the remote acquisition of physiological and behavioral biomarkers in psychiatric clinical research. J Psychiatr Res. 2017 Feb;85:1-14. [PMID: 27814455]

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QUESTiON 5: WHAT KiNDS OF SERViCES AND SUPPORTS ARE NEEDED TO MAxiMiZE QUALiTY OF LiFE FOR PEOPLE ON THE AUTiSM SPECTRUM?

1. Office of Autism Research Coordination, National 7. Boyd BA, Hume K, McBee MT, Alessandri M, Institute of Mental Health, on behalf of the Interagency Gutierrez A, Johnson L, Sperry L, Odom SL. Comparative Autism Coordinating Committee (IACC). 2014-2015 efficacy of LEAP, TEACCH and non-model-specific IACC Autism Spectrum Disorder Research Portfolio special education programs for preschoolers with Analysis Report. October 2017. Retrieved from the autism spectrum disorders. J Autism Dev Disord. 2014 U.S. Department of Health and Human Services Feb;44(2):366-80. [PMID: 23812661] Interagency Autism Coordinating Committee website: https://iacc.hhs.gov/portfolio-analysis/2015/ 8. Levy SE, Giarelli E, Lee LC, Schieve LA, Kirby RS, index.shtml Cunniff C, Nicholas J, Reaven J, Rice CE. Autism spectrum disorder and co-occurring developmental, 2. Shattuck PT, Roux AM, Hudson LE, Taylor JL, psychiatric, and medical conditions among children in Maenner å, Trani JF. Services for adults with multiple populations of the United States. J Dev Behav an autism spectrum disorder. Can J Psychiatry. Pediatr. 2010 May;31(4):267-75. [PMID: 20431403] 2012 May;57(5):284-91. [PMID: 22546060] 9. Muris P, Steerneman P, Merckelbach H, Holdrinet I, 3. United States Government Accountability Office Meesters C. Comorbid anxiety symptoms in children (GAO). Youth with Autism: Round Table Views of with pervasive developmental disorders. J Anxiety Services Needed During the Transition into Adulthood. Disord. 1998 Jul-Aug;12(4):387-93. [PMID: 9699121] Oct 2016. Retrieved from: https://www.gao.gov/ assets/690/680525.pdf 10. Mattila ML1, Hurtig T, Haapsamo H, Jussila K, Kuusikko-Gauffin S, Kielinen M, Linna SL, Ebeling H, 4. United States Government Accountability Office Bloigu R, Joskitt L, Pauls DL, Moilanen I. Comorbid (GAO). Youth with Autism: Federal Agencies Should psychiatric disorders associated with Asperger Take Additional Action to Support Transition-Age Youth. syndrome/high-functioning autism: a community- May 2017. Retrieved from: https://www.gao.gov/ and clinic-based study. J Autism Dev Disord. assets/690/684484.pdf 2010 Sep;40(9):1080-93. [PMID: 20177765]

5. Buescher AV, Cidav Z, Knapp M, Mandell DS. 11. Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Costs of autism spectrum disorders in the United Morgan J, Tager-Flusberg H, Lainhart JE. Comorbid Kingdom and the United States. JAMA Pediatr. psychiatric disorders in children with autism: interview 2014 Aug;168(8):721-8. [PMID: 24911948] development and rates of disorders. J Autism Dev Disord. 2006 Oct;36(7):849-61. [PMID: 16845581] 6. Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. Economic burden of childhood autism spectrum disorders. Pediatrics. 2014 Mar;133(3):e520-9. [PMID: 24515505]

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12. Kraper CK, Kenworthy L, Popal H, Martin A, 19. Shattuck PT, Narendorf SC, Cooper B, Sterzing Wallace GL. The Gap Between Adaptive Behavior and PR, Wagner M, Taylor, JL. Postsecondary Intelligence in Autism Persists into Young Adulthood education and employment among youth with and is Linked to Psychiatric Co-morbidities. J Autism an autism spectrum disorder. Pediatrics. Dev Disord. 2017 Jul 14. [PMID: 28710532] 2012 Jun;129(6):1042-9. [PMID: 22585766]

13. Gotham K, Brunwasser SM, Lord C. Depressive 20. Golnik A, Maccabee-Ryaboy N, Scal P, Wey A, and anxiety symptom trajectories from school age Gaillard P. Shared decision making: improving care through young adulthood in samples with autism for children with autism. Intellect Dev Disabil. 2012 spectrum disorder and developmental delay. J Am Aug;50(4):322-31. [PMID: 22861133] Acad Child Adolesc Psychiatry. 2015 May;54(5): 369-76.e3. [PMID: 25901773] 21. Mandell DS, Barry CL, Marcus SC, Xie M, Shea K, Mullan K, Epstein AJ. Effects of Autism Spectrum 14. Cassidy S, Bradley P, Robinson J, Allison C, McHugh, Disorder Insurance Mandates on the Treated M, Baron-Cohen, S. Suicidal ideation and suicide Prevalence of Autism Spectrum Disorder. JAMA Pediatr. plans or attempts in adults with Asperger's syndrome 2016 Sep 1;170(9):887-93. [PMID: 27399053] attending a specialist diagnostic clinic: a clinical cohort study. Lancet Psychiatry. 2014 Jul;1(2):142-7. 22. Leslie DL, Iskandarani K, Dick AW, Mandell DS, [PMID: 26360578] Yu H, Velott D, Agbese E, Stein BD. The Effects of Medicaid Home and Community-Based Services 15. Cassidy S, Rodgers J. Understanding and Waivers on Unmet Needs Among Children prevention of suicide in autism. Lancet Psychiatry. with Autism Spectrum Disorder. Med Care. 2017 2017 Jun;4(6):e11. [PMID: 28551299] Jan;55(1):57-63. [PMID: 27547947]

16. Pelton MK, Cassidy SA. Are autistic traits 23. Cidav Z, Marcus SC, Mandell DS. Home- and associated with suicidality? A test of the Community-Based Waivers for Children with Autism: interpersonal-psychological theory of suicide Effects on Service Use and Costs. Intellect Dev Disabil. in a non-clinical young adult sample. Autism 2014 Aug;52(4):239-48. [PMID: 25061768] Res. 2017 Jul 7. [PMID: 28685996] 24. Centers for Medicare & Medicaid Services. Report 17. Croen LA, Zerbo O, Qian Y, Massolo ML, Rich S, on State Services to Individuals with Autism Spectrum Sidney S, Kripke C. The health status of adults on the Disorders (ASD). 2011 Apr. https://www.cms.gov/ autism spectrum. Autism. 2015 Oct;19(7):814-23. apps/files/9-state-report.pdf [PMID: 25911091] 25. Bilder D, Botts EL, Smith KR, Pimentel R, Farley M, 18. Nahmias AS, Kase C, Mandell DS. Comparing Viskochil J, McMahon WM, Block H, Ritvo E, cognitive outcomes among children with autism Ritvo RA, Coon H. Excess mortality and causes of spectrum disorders receiving community-based death in autism spectrum disorders: a follow up of early intervention in one of three placements. the 1980s Utah/UCLA autism epidemiologic study. Autism. 2014 Apr;18(3):311-20. [PMID: 23188885] J Autism Dev Disord. 2013 May;43(5):1196-204. [PMID: 23008058]

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26. Zablotsky B, Pringle BA, Colpe LJ, Kogan MD, Rice 32. Zhang W, Mason AE, Boyd B, Sikich L, Baranek G. C, Blumberg, SJ. Service and treatment use among A Rural-Urban Comparison in Emergency Department children diagnosed with autism spectrum disorders. Visits for U.S. Children with Autism Spectrum Disorder. J Dev Behav Pediatr. 2015 Feb-Mar;36(2):98-105. J Autism Dev Disord. 2017 Mar;47(3):590-598. [PMID: 25650952] [PMID: 27909850]

27. Battaglia M, Detrick S, Fernandez A. Multidisciplinary 33. Sohl K, Mazurek M, Brown, R. ECHO Autism: Treatment for Adults with Autism Spectrum Disorder Using Technology and Mentorship to Bridge Gaps, and Co-Occurring Mental Health Disorders: Adapting Increase Access to Care, and Bring Best Practice Clinical Research Tools to Everyday Clinical Practice. Autism Care to Primary Care. Clin Pediatr (Phila). Journal of Mental Health Research in Intellectual 2017 Jun;56(6):509-511. [PMID: 28497714] Disabilities. June 2016; 9(4), 232-249. http://dx.doi. org/10.1080/19315864.2016.1192708 34. Liptak GS, Benzoni LB, Mruzek DW, Nolan KW, Thingvoll MA, Wade CM, Fryer GE. Disparities 28. Posserud M, Hysing M, Helland W, Gillberg C, in diagnosis and access to health services for Lundervold AJ. Autism traits: The importance of children with autism: Data from the National Survey "co-morbid" problems for impairment and contact with of Children’s Health. J Dev Behav Pediatr. 2008 services. Data from the Bergen Child Study. Res Dev Jun;29(3):152-60. [PMID: 18349708] Disabil. 2016 Jan 27. pii: S0891-4222(16)30002-6. [PMID: 26826893] 35. Oswald DP, Haworth SM. (2016). Autism spectrum disorders. In Handbook of Mental Health 29. Hirvikoski T, Mittendorfer-Rutz E, Boman M, in African American Youth (pp. 271-285). Springer Larsson H, Lichtenstein P, Bölte S. Premature mortality International Publishing. in autism spectrum disorder. Br J Psychiatry. 2016 Mar;208(3):232-8. [PMID: 26541693] 36. Frieden TR, Jaffe HW, Cono J, Richards CL, Iademarco MF. Prevalence of autism spectrum 30. National Autism Association. Mortality & Risk in disorder among children aged 8 years—Autism and ASD Wandering/Elopement 2011-2016. March 2017. developmental disabilities monitoring network, Retrieved from: http://nationalautismassociation. 11 sites, United States, 2010. MMWR Surveill Summ. org/wp-content/uploads/2017/04/NAA 2014 Mar 28;63(2):1-21. [PMID: 24670961] MortalityRiskASDElopement.pdf 37. Mandell DS, Wiggins LD, Carpenter LA, Daniels J, 31. Liu G, Pearl AM, Kong L, Leslie DL, Murray MJ. DiGuiseppi C, Durkin MS, Giarelli E, Morrier MJ, A Profile on Emergency Department Utilization in Nicholas JS, Pinto-Martin JA, Shattuck PT, Thomas Adolescents and Young Adults with Autism KC, Yeargin-Allsopp M, Kirby RS. Racial/ethnic Spectrum Disorders. J Autism Dev Disord. 2017 disparities in the identification of children with Feb;47(2):347-358. [PMID: 27844247] autism spectrum disorders. Am J Public Health. 2009 Mar;99(3):493-8. [PMID: 19106426]

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38. Zamora I, Williams ME, Higareda M, Wheeler BY, 45. Sim A, Vaz S, Cordier R, Joosten A, Parsons D, Smith Levitt P. Brief report: Recruitment and retention of C, Falkmer T. Factors associated with stress in families minority children for autism research. J Autism Dev of children with autism spectrum disorder. Dev Disord. 2016 Feb;46(2):698-703. [PMID: 26404703] Neurorehabil. 2017 Jun 9:1-11. [PMID: 28598245]

39. Magaña S, Lopez K, Aguinaga A, Morton H. 46. Cowen PS, Reed DA. Effects of respite care for children Access to diagnosis and treatment services among with developmental disabilities: evaluation of an latino children with autism spectrum disorders. intervention for at risk families. Public Health Nurs. Intellect Dev Disabil. 2013 Jun;51(3):141-53. 2002 Jul-Aug;19(4):272-83. [PMID: 12071901] [PMID: 23834211] 47. Mandell DS, Xie M, Morales KH, Lawer L, 40. Magaña S, Parish SL, Son E. Have racial and McCarthy M, Marcus SC. The interplay of ethnic disparities in the quality of health care outpatient services and psychiatric hospitalization relationships changed for children with developmental among Medicaid-enrolled children with autism disabilities and ASD? Am J Intellect Dev Disabil. 2015 spectrum disorders. Arch Pediatr Adolesc Med. 2012 Nov;120(6):504-13. [PMID: 26505871] Jan;166(1):68-73. [PMID: 22213753]

41. Baker J, Sanghvi T, Hajeebhoy N, Martin L, 48. Dykens EM, Fisher MH, Taylor JL, Lambert W, Lapping K. Using an evidence-based approach Miodrag N. Reducing distress in mothers of children to design large-scale programs to improve infant with autism and other disabilities: a randomized and young child feeding. Food Nutr Bull. 2013 trial. Pediatrics. 2014 Aug;134(2):e454-63. Sep;34(3 Suppl):S146-55. [PMID: 24261073] [PMID: 25049350]

42. Cooper BR, Bumbarger BK, Moore JE. Sustaining 49. Bearss K, Johnson C, Smith T, Lecavalier L, Swiezy evidence-based prevention programs: Correlates in N, Aman M, McAdam DB, Butter E, Stillitano C, a large-scale dissemination initiative. Prev Sci. 2015 Minshawi N, Sukhodolsky DG, Mruzek DW, Turner Jan;16(1):145-57. [PMID: 23975240] K, Neal T, Hallett V, Mulick JA, Green B, Handen B, Deng Y, Dziura J, Scahill L. Effect of parent training 43. Hiersteiner D, Bradley V, Ne'eman A, Bershadsky J, vs parent education on behavioral problems in children Bonardi A. Putting the Research in Context: The Life with autism spectrum disorder: a randomized Experience and Outcomes of Adults on the Autism clinical trial. JAMA. 2015 Apr 21;313(15):1524-33. Spectrum Receiving Services in 29 States. Inclusion. [PMID: 25898050] 2017;5(1), 45-59. 50. Pickard KE, Ingersoll BR. Quality versus quantity: 44. Schieve LA, Blumberg SJ, Rice C, Visser SN, Boyle The role of socioeconomic status on parent- C. The relationship between autism and parenting reported service knowledge, service use, unmet stress. Pediatrics. 2007 Feb;119 Suppl 1:S114-21. service needs, and barriers to service use. Autism. [PMID: 17272578] 2016 Jan;20(1):106-15. [PMID: 25948601]

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51. Roux AM, Shattuck PT, Rast JE, Rava JA, 55. Stahmer AC, Aarons GA. Attitudes toward Anderson KA. National Autism Indicators Report: adoption of evidence-based practices: A comparison transition into young adulthood. Philadelphia, PA: of autism early intervention providers and Life Course Outcomes Research Program, AJ Drexel children’s mental health providers. Psychol Serv . Autism Institute, Drexel University. April 2015. 2009 Aug;6(3):223-234. [PMID: 21796262] Retrieved from: http://drexel.edu/autismoutcomes/ publications-and-reports/publications/ 56. Stahmer A, Reed S, Shin S, Mandell D. (2010). National-Autism-Indicators-Report-Transition- Fidelity of implementation of evidence-based to-Adulthood/#sthash.p272LoRy.dpbs practice in community classrooms. In Presentation at the 9th international meeting for autism research 52. Taylor JL, Henninger NA. Frequency and correlates (IMFAR). of service access among youth with autism transitioning to adulthood. J Autism Dev Disord. 2015 57. Fueyo M, Caldwell T, Mattern SB, Zahid J, Foley T. Jan;45(1):179-91. [PMID: 25081594] The health home: a service delivery model for autism and intellectual disability. Psychiatr Serv. 53. Turcotte P, Mathew M, Shea LL, Brusilovskiy E, 2015 Nov;66(11):1135-7. [PMID: 26129999] Nonnemacher SL. Service needs across the lifespan for individuals with autism." J Autism Dev Disord. 58. United States Government Accountability Office 2016 Jul;46(7):2480-9. [PMID: 27084080] (GAO). STUDENTS WITH DISABILITIES: Better Federal Coordination Could Lessen Challenges in 54. Koffer Miller K H, Mathew M, Nonnemacher the Transition from High School. July 2012. SL, Shea LL. (2017). Program experiences Retrieved from: http://www.gao.gov/assets/ of adults with autism, their families, and 600/592329.pdf providers: Findings from a focus group study. Autism. doi:10.1177/1362361316679000

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QUESTiON 6: HOW CAN WE MEET THE NEEDS OF PEOPLE WiTH ASD AS THEY PROGRESS iNTO AND THROUGH ADULTHOOD?

1. Shattuck PT, Steinberg J, Yu J, Wei X, Cooper BP, 6. Orsmond GI, Shattuck PT, Cooper BP, Sterzing PR, Newman L, Roux AM. Disability Identification Anderson KA. Social participation among young and Self-Efficacy among College Students on adults with an autism spectrum disorder. J Autism Dev the Autism Spectrum. Autism Res Treat. Disord. 2013 Nov;43(11):2710-9. [PMID: 23615687] 2014;2014:924182. [PMID: 24707401] 7. Taylor JL, Seltzer MM. Change in the autism 2. Christensen DL, Baio J, Van Naarden Braun K, Bilder phenotype during the transition to adulthood. D, Charles J, Constantino JN, Daniels J, Durkin MS, J Autism Dev Disord. 2010 Dec;40(12):1431-1446. Fitzgerald RT, Kurzius-Spencer M, Lee LC, Pettygrove [PMID: 20361245] S, Robinson C, Schulz E, Wells C, Wingate MS, Zahorodny W, Yeargin-Allsopp M. Prevalence 8. Burgess S, Cimera RE. Employment Outcomes and Characteristics of Autism Spectrum Disorder of Transition-Aged Adults With Autism Spectrum Among Children Aged 8 Years–Autism and Disorders : A State of the States Report. Developmental Disabilities Monitoring Network, 11 Am J Intellect Dev Disabil. 2014 Jan;119(1):64-83. Sites, United States, 2012. MMWR Surveill Summ. [PMID: 24450322] 2016 Apr 1;65(3):1-23. [PMID: 27031587] 9. Gobbo K, Shmulsky S. Faculty Experience with 3. Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, College Students With Autism Spectrum Wagner M, Taylor JL. Postsecondary education and Disorders: A Qualitative Study of Challenges and employment among youth with an autism spectrum Solutions. Focus on Autism and Other Developmental disorder. Pediatrics. 2012 Jun;129(6):1042-9. Disabilities. 2014 March. 29(1), 13–22. http://doi. [PMID: 22585766] org/10.1177/1088357613504989

4. Taylor JL, Seltzer MM. Employment and post- 10. Roux AM, Shattuck PT, Rast JE, Rava JA, and secondary educational activities for young adults Anderson KA. National Autism Indicators Report: with Autism Spectrum Disorders during the Transition into Young Adulthood. Philadelphia, PA: transition to adulthood. J Autism Dev Disord. 2011 Life Course Outcomes Research Program, A.J. May;41(5):566-74. [PMID: 20640591] Drexel Autism Institute, Drexel University. April 2015. Retrieved from: http://drexel.edu/ 5. Shattuck PT, Wagner M, Narendorf S, Sterzing P, autismoutcomes/publications-and-reports/ Hensley M. Post-High School Service Use among publications/National-Autism-Indicators- Young Adults with an Autism Spectrum Disorder. Report-Transition-to-Adulthood/#sthash. Arch Pediatr Adolesc Med. 2011 Feb;165(2):141-6. p272LoRy.dpbs [PMID: 21300654]

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11. Ellison M, Clark J, Cunningham M, Hansen R. 17. Smith LE, Greenberg JS, Mailick MR. The family Academic and campus accommodations that foster context of autism spectrum disorders: Influence on success for college students with Asperger’s Disorder. the behavioral phenotype and quality of life. Child Southern Regional Council on Educational Administration Adolesc Psychiatr Clin N Am. 2014 Jan;23(1):143-55. 2013 Yearbook: Jazzing It Up. 2013 Sept; 65–76. [PMID: 24231173]

12. Myers E, Davis B.E, Stobbe G, Bjornson K. 18. White SW, Richey JA, Gracanin D, Coffman M, Community and social participation among Elias R, LaConte S, Ollendick TH. Psychosocial and individuals with autism spectrum disorder computer-assisted intervention for college students transitioning to adulthood. J Autism Dev Disord. with autism spectrum disorder: Preliminary support 2015 Aug;45(8):2373-81. [PMID: 25725812] for feasibility. Educ Train Autism Dev Disabil. 2016 Sep;51(3):307-317. [PMID: 28111607] 13. Taylor JL, Adams RA, Bishop SL. Social participation and its relation to internalizing symptoms 19. Wehman P, Schall CM, McDonough J, Graham C, among youth with autism spectrum disorder as Brooke V, Riehle JE, Brooke A, Ham W, Lau S, Allen J, they transition from high school. Autism Res. 2017 Avellone L. Effects of an employer-based intervention Apr;10(4):663-672. [PMID: 27739234] on employment outcomes for youth with significant support needs due to autism. Autism. 14. Tobin M, Drager K, Richardson L. A systematic 2017 Apr;21(3):276-290. [PMID: 27154907] review of social participation for adult with autism spectrum disorders: Support, social functioning, and 20. Laugeson EA, Gantman A, Kapp SK, Orenski K, quality of life. Research in Autism Spectrum Disorders. Ellingson R. A randomized controlled trial to 2014 Mar; 8(3), 214-229. https://doi.org/10.1016/ improve social skills in young adults with autism j.rasd.2013.12.002 spectrum disorder: The UCLA PEERS program. J Autism Dev Disord. 2015 Dec;45(12):3978-89. 15. Anderson KA, Shattuck PT, Cooper BP, Roux [PMID: 26109247] AM, Wagner M. Prevalence and correlates of postsecondary residential status among young 21. Morgan L, Leatzow A. Clark S, Siller M. Interview skills adults with an autism spectrum disorder. Autism. for adults with autism spectrum disorder: A pilot 2014 Jul;18(5):562-70. [PMID: 23996904] randomized controlled trial. J Autism Dev Disord. 2014 Sep;44(9):2290-300. [PMID: 24682707] 16. Taylor JL, Hodapp RM, Burke MM, Waitz-Kudla SN, Rabideau C. Training parents of youth 22. Smith MJ, Ginger E, Wright K, Wright M, Taylor with autism spectrum disorder to advocate for JL, Humm LB, Olson D, Bell MD, Fleming MF. adult disability services: Results from a pilot Virtual reality job interview training in adults with randomized controlled trial. J Autism Dev Disord. autism spectrum disorder. J Autism Dev Disord. 2017 Mar;47(3):846-857. [PMID:28070786] 2014 Oct;44(10):2450-63. [PMID: 24803366]

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23. Wehman P, Brooke V, Brooke AM, Ham W, 30. Lakin KC, Doljanac R, Byun SY, Stancliffe RJ, Taub Schall C, McDonough J, Lau S, Seward H. Avellone L. S, Chiri G. Factors associated with expenditures Employment for adults with autism spectrum for Medicaid home and community based services disorders: A retrospective review of a customized (HCBS) and intermediate care facilities for persons employment approach. Res Dev Disabil. 2016 with mental retardation (ICF/MR) services Jun-Jul;53-54:61-72. [PMID: 26855048] for persons with intellectual and developmental disabilities. Intellect Dev Disabil. 2008 Jun;46(3): 24. Anderson DK, Liang JW, Lord C. Predicting young 200-14. [PMID: 18578578] adult outcome among more and less cognitively able individuals with autism spectrum disorders. 31. McConkey R, Abbott S, Walsh PN, Linehan C, Emerson J Child Psychol Psychiatry. 2014 May;55(5):485-94. E. Variations in the social inclusion of people with [PMID: 24313878] intellectual disabilities in supported living schemes and residential settings. J Intellect Disabil Res. 2007 25. Howlin P, Moss P, Savage S, Rutter M. Social Mar;51(Pt 3):207-17. [PMID: 17300416] outcomes in mid- to later adulthood among individuals diagnosed with autism and average nonverbal IQ 32. Tichá R, Hewitt A, Nord D, Larson S. System and as children. J Am Acad Child Adolesc Psychiatry. 2013 individual outcomes and their predictors in services Jun;52(6):572-81.e1. [PMID: 23702446] and support for people with IDD. Intellect Dev Disabil. 2013 Oct;51(5):298-315. [PMID: 24303819] 26. Taylor JL, Seltzer MM. Developing a vocational index for adults with autism spectrum disorders. 33. Verheij C, Louwerse A, van der Ende J, Eussen MLJM, J Autism Dev Disord. 2012;42(12):2669-2679. Van Gool AR, Verheij F, Verhulst FC, Greaves-Lord K. [PMID: 22466690] The stability of comorbid psychiatric disorders: A 7 year follow up of children with pervasive developmental 27. Taylor JL, Henninger NA, Mailick MR. Longitudinal disorder-not otherwise specified. J Autism Dev Disord. patterns of employment and postsecondary 2015 Dec;45(12):3939-48. [PMID: 26456972] educational activities for adults with ASD and normal-range IQ. Autism. 2015 Oct;19(7):785-793. 34. Croen LA, Zerbo O, Qian Y, Massolo ML, Rich S, [PMID: 26019306] Sidney S, Kripke C. The health of adults on the autism spectrum. Autism. 2015 Oct;19(7):814-23. 28. Wei X, Wagner M, Hudson L, Yu JW, Shattuck P. [PMID: 25911091] Transition to adulthood: Employment, education, and disengagement in individuals with autism spectrum 35. Gotham K, Brunwasser SM, Lord C. Depressive disorder. Emerging Adulthood. 2015 Feb; 3(1), 37-45. and anxiety symptom trajectories from school age https://doi.org/10.1177/2167696814534417 through young adulthood in samples with autism spectrum disorder and developmental delay. 29. Taylor JL, Mailick MR. A Longitudinal Examination of J Am Acad Child Adolesc Psychiatry. 2015 May;54(5): 10-Year Change in Vocational and Educational Activities 369-76.e3. [PMID: 25901773] for Adults With Autism Spectrum Disorders. Dev Psychol. 2014 Mar; 50 (3): 699-708. [PMID: 24001150]

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36. Gotham K, Marvin AR, Taylor JL, Warren Z, Anderson 43. Liu G, Pearl AM, Kong L, Leslie DL, Murray MJ. CM, Law PA, Law JK, Lipkin PH. Characterizing the A Profile on Emergency Department Utilization daily life, needs, and priorities of adults with autism in Adolescents and Young Adults with Autism spectrum disorder from Interactive Autism Spectrum Disorders. J Autism Dev Disord. 2017 Network data. Autism. 2015 Oct;19(7):794-804. Feb;47(2):347-358. [PMID: 27844247] [PMID: 25964655] 44. Nicolaidis C, Raymaker D, McDonald K, Dern S, 37. Maddox BB, White SW. Comorbid social anxiety Boisclair WC, Ashkenazy E, Baggs A. Comparison of disorder in adults with autism spectrum disorder. Healthcare Experiences in Autistic and Non-Autistic J Autism Dev Disord. 2015 Dec;45(12):3949-60. Adults: A Cross-Sectional Online Survey Facilitated [PMID: 26243138] by an Academic-Community Partnership. J Gen Intern Med. 2013 Jun;28(6):761-9. [PMID: 23179969] 38. Kraper CK, Kenworthy L, Popal H, Martin A, Wallace GL. The Gap Between Adaptive Behavior and 45. Raymaker DM, McDonald KE, Ashkenazy E, Gerrity Intelligence in Autism Persists into Young Adulthood M, Baggs AM, Kripke C, Hourston S, Nicolaidis C. and is Linked to Psychiatric Co-morbidities. J Autism Barriers to healthcare: Instrument development and Dev Disord. 2017 Jul 14. [Epub ahead of print] comparison between autistic adults and adults with [PMID: 28710532] and without other disabilities. Autism. 2016 Sep 22. [Epub ahead of print] [PMID: 27663266] 39. Hirvikoski T, Mittendorfer-Rutz E, Boman M, Larsson H, Lichtenstein P, Bölte S. Premature mortality in autism 46. Pickett J, Xiu E, Tuchman R, Dawson G, Lajonchere spectrum disorder. The British Journal of Psychiatry. C. Mortality in individuals with autism, with and 2016;208(3):232-238. without epilepsy. J Child Neurol. 2011 Aug;26(8): 932-9. [PMID: 21471551] 40. Cashin A, Buckley T, Trollor JN, Lennox N. A scoping review of what is known of the physical health of 47. Gillberg C, Billstedt E, Sundh V, Gillberg IC. adults with autism spectrum disorder. Br J Psychiatry. Mortality in autism: a prospective longitudinal 2016 Mar;208(3):232-8. [PMID: 26541693] community-based study. J Autism Dev Disord. 2010 Mar;40(3):352-7. [PMID: 19838782] 41. Rengit AC, McKowen JW, O'Brien J, Howe YJ, McDougle CJ. Brief Report: Autism Spectrum Disorder 48. Bilder D, Botts EL, Smith KR, Pimentel R, Farley M, and Substance Use Disorder: A Review and Case Viskochil J, McMahon WM, Block H, Ritvo E, Ritvo Study. J Autism Dev Disord. 2016 Jul;46(7):2514-9. RA, Coon H. Excess mortality and causes of death [PMID: 26944591] in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study. 42. Vohra R, Madhavan S, Sambamoorthi U. Emergency J Autism Dev Disord. 2013 May;43(5):1196-204. Department Use Among Adults with Autism [PMID: 23008058] Spectrum Disorders (ASD). J Autism Dev Disord. 2016 Apr;46(4):1441-54. [PMID: 26762115]

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49. Guan J, Li G. Injury mortality in individuals with 57. Dworzynski K, Ronald A, Bolton P, Happé F. autism. Am J Public Health. 2017 May;107(5):791-793. How different are girls and boys above and below [PMID: 28323463] the diagnostic threshold for autism spectrum disorders? J Am Acad Child Adolesc Psychiatry. 2012 50. Hategan A, Bourgeois JA, Goldberg J. Aging with Aug;51(8):788-97. [PMID: 22840550] autism spectrum disorder: an emerging public health problem. Int Psychogeriatr. 2017 Apr;29(4):695-697. 58. Loomes R, Hull L, Mandy WPL. What Is the [PMID: 27669633] Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis. J Am Acad 51. Piven J, Rabins P. Autism spectrum disorders in older Child Adolesc Psychiatry. 2017 Jun;56(6):466-474. adults: toward defining a research agenda. J Am Geriatr [PMID: 28545751] Soc. 2011 Nov;59(11):2151-5. [PMID: 22091837] 59. Shattuck PT, Seltzer MM, Greenberg JS, 52. Lever AG, Geurts HM. Age-related differences Orsmond GI, Bolt D, Kring S, Lounds J, Lord C. in cognition across the adult lifespan in autism Change in autism symptoms and maladaptive spectrum disorder. Autism Res. 2016 Jun;9(6): behaviors in adolescents and adults with an autism 666-76. [PMID: 26333004] spectrum disorder. J Autism Dev Disord. 2007 Oct;37(9):1735-47. [PMID: 17146700] 53. White SW, DiCriscio AS. Introduction to special issue ASD in adulthood: Comorbidity and intervention. 60. McGovern CW, Sigman M. Continuity and change J Autism Dev Disord. 2015 Dec;45(12):3905-7. from early childhood to adolescence in autism. [PMID: 26519326] J Child Psychol Psychiatry. 2005 Apr;46(4):401-8. [PMID: 15819649] 54. Cheak-Zamora NC, Teti M, Maurer-Batjer A, Halloran D. Snapshots of growing up: Youth with autism explore 61. Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL, adulthood through Photovoice. J Dev Behav Pediatr. DiLavore P, Pickles A, Rutter M. The autism diagnostic 2016 Jul-Aug;37(6):433-41. [PMID: 27355880] observation schedule-generic: a standard measure of social and communication deficits associated with Rutter M , Greenfeld D, Lockyer L. A five to 55. the spectrum of autism. J Autism Dev Disord. 2000 fifteen year follow-up study of infantile psychosis. Jun;30(3):205-23. [PMID: 11055457] Br J Psychiatry. 1967 Nov;113(504):1183-99. [PMID: 6075452] 62. Hus V, Lord C. The Autism Diagnostic Observation Schedule, Module 4: Revised Algorithm and Brugha TS, McManus S, Bankart J, Scott F, Purdon 56. Standardized Severity Scores. J Autism Dev Disord. S, Smith J, Bebbington P, Jenkins R, Meltzer H. 2014 Aug;44(8):1996-2012. [PMID: 24590409] Epidemiology of autism spectrum disorders in adults in the community in England. Arch Gen Psychiatry. 63. Pugliese CE, Kenworthy L, Bal VH, Wallace GL, 2011 May;68(5):459-65. [PMID: 21536975] Yerys BE, Maddox BB, White SW, Popal H, Armour AC, Miller J, Herrington JD, Schultz RT, Martin A, Anthony LG. Replication and comparison of the

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newly proposed ADOS-2, module 4 algorithm in ASD Disabilities up to 8 Years After High School. A Report without ID: A multi-site study. J Autism Dev Disord. From the National Longitudinal Transition Study-2 2015 Dec;45(12):3919-31. [PMID: 26385796] (NLTS2) (NCSER 2011-3005). Menlo Park, CA: SRI International. Retrieved from: https://ies.ed.gov/ 64. Schultz R. “Digital Clinical Assessment for Diagnosis ncser/pubs/20113005/pdf/20113005.pdf and Treatment Outcome Measurement.” Interagency Autism Coordinating Committee Meeting, 71. Helverschou SB, Rasmussen K, Steindal K, 26 April 2017, National Institutes of Health, MD. Søndanaa E, Nilsson B, Nøttestad JA. Offending Panel Presentation. profiles of individuals with autism spectrum disorder: A study of all individuals with autism spectrum 65. Geurts HM, Jansen MD. A retrospective chart study: disorder examined by the forensic psychiatric service the pathway to a diagnosis for adults referred for in Norway between 2000 and 2010. Autism. 2015 ASD assessment. Autism. 2012 May;16(3):299-305. Oct;19(7):850-8. [PMID: 25976157] [PMID: 21949003] 72. Crane L, Maras KL, Hawken T, Mulcahy S, Memon 66. Anderson C, Law JK, Daniels A, Rice C, Mandell A. Experiences of Autism Spectrum Disorder and DS, Hagopian L, Law PA. Occurrence and Family Policing in England and Wales: Surveying Police and Impact of Elopement in Children With Autism the Autism Community. J Autism Dev Disord. 2016 Spectrum Disorders. Pediatrics. 2012 Nov;130(5): Jun;46(6):2028-41. [PMID: 26861714] 870-7. [PMID: 23045563] 73. Taylor JL, Gotham K. Cumulative life events, 67. Humphrey N, Symes W. Peer interaction patterns traumatic experiences, and psychiatric among adolescents with autistic spectrum disorders symptomatology in transition-aged youth with (ASDs) in mainstream school settings. Autism. 2011 autism spectrum disorder. J Neurodev Disord. Jul;15(4):397-419. [PMID: 21454385] 2016 Jul 27;8:28. [PMID: 27468315]

68. Bancroft K, Batten A, Lambert S, Madders T. The way 74. Howlin P, Magiati I. Autism spectrum disorder: we are: autism in 2012. The National Autistic Society. Outcomes in adulthood. Curr Opin Psychiatry. 2017 (2012). Retrieved from: http://library.autism.org.uk/ Mar;30(2):69-76. [PMID: 28067726] Portal/Default/en-GB/RecordView/Index/28271 75. Pearpoint J, O'Brien J, Forest M. Path: 69. Brown-Lavoie SM, Viecili MA, Weiss JA. Sexual Planning Alternative Tomorrows with Hope for knowledge and victimization in adults with autism Schools, Organizations, Business, Families: spectrum disorders. J Autism Dev Disord. 2014 A Workbook for Planning Positive Possible Futures. Sep;44(9):2185-96. [PMID: 24664634] Inclusion Press, 1993.

70. Newman L, Wagner M, Knokey A-M, Marder C, 76. Vandercook T, York J, Forest M. The McGill Action Nagle K, Shaver D, Wei X with Cameto R, Contreras Planning System (MAPS): A strategy for building the E, Ferguson K, Greene S, Schwarting M (2011). vision. Journal of the Association for Persons with Severe The Post-High School Outcomes of Young Adults With Handicaps. 1989; 14(3), 205-215.

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77. Starkstein S, Gellar S, Parlier M, Payne L, Piven J. 81. Burke MM, Patton KA, Taylor JL. Family support: A High rates of parkinsonism in adults with autism. review of the literature on families of adolescents with J Neurodev Disord. 2015;7(1):29. [PMID: 26322138] disabilities. Journal of Family Social Work. 2016; 19(4), 252-285. DOI: 10.1080/10522158.2016.1214658. 78. Geurts HM, Vissers ME. Elderly with autism: executive functions and memory. J Autism Dev Disord. 82. Nicholas DB, Attridge M, Zwaigenbaum L, Clarke M. 2012 May;42(5):665-75. [PMID: 21656030] Vocational support approaches in autism spectrum disorder: A synthesis review of the literature. Autism. 79. Tint A, Maughan A, Weiss J. Community 2015 Feb;19(2):235-45. [PMID: 24449603] participation of youth with intellectual disability and autism spectrum disorder. J Intellect Disabil Res. 83. Office of Autism Research Coordination, National 2017 Feb;61(2):168-180. [PMID: 27492816] Institute of Mental Health, on behalf of the Interagency Autism Coordinating Committee (IACC). 2014-2015 80. Seltzer MM, Greenberg JS, Hong J, Smith LE, IACC Autism Spectrum Disorder Research Portfolio Almeida DM, Coe C, Stawski RS. Maternal cortisol Analysis Report. October 2017. Retrieved from the levels and behavior problems in adolescents U.S. Department of Health and Human Services and adults with ASD. J Autism Dev Disord. 2010 Interagency Autism Coordinating Committee website: Apr;40(4):457-69. [PMID: 19890706] https://iacc.hhs.gov/portfolio-analysis/2015/ index.shtml

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QUESTiON 7: HOW DO WE CONTiNUE TO BUiLD, ExPAND, AND ENHANCE THE iNFRASTRUCTURE SYSTEM TO MEET THE NEEDS OF THE ASD COMMUNiTY?

1. Nichols L, Freund M, Ng C, Kau A, Parisi M, Taylor A, 7. Brugha TS, McManus S, Bankart J, Scott F, Purdon S, Armstrong D, Avenilla F, Joseph J, Meinecke D, Smith J, Bebbington P, Jenkins R, Meltzer H. Wagner A, Roger Little A. The National Institutes of Epidemiology of autism spectrum disorders in adults Health NeuroBioBank: a federated national network in the community in England. Arch Gen Psychiatry. of human brain and tissue repositories. Biol Psychiatry. 2011 May;68(5):459-65. [PMID: 21536975] 2014 Jun 15;75(12):e21-2. [PMID: 24074636] 8. Christensen DL, Baio J, Van Naarden Braun K, Bilder 2. Johnson SB, Whitney G, McAuliffe M, Wang H, D, Charles J, Constantino JN, Daniels J, Durkin MS, McCreedy E, Rozenblit L, Evans CC. Using global Fitzgerald RT, Kurzius-Spencer M, Lee LC, Pettygrove unique identifiers to link autism collections. J Am Med S, Robinson C, Schulz E, Wells C, Wingate MS, Inform Assoc. 2010 Nov-Dec;17(6):689-95. Zahorodny W, Yeargin-Allsopp M; Centers for [PMID: 20962132] Disease Control and Prevention (CDC). Prevalence and Characteristics of Autism Spectrum Disorder 3. Buxbaum JD, Daly MJ, Devlin B, Lehner T, Roeder Among Children Aged 8 Years--Autism and K, State MW; Autism Sequencing Consortium. Developmental Disabilities Monitoring Network, The autism sequencing consortium: large-scale, 11 Sites, United States, 2012. MMWR Surveill Summ. high-throughput sequencing in autism spectrum 2016 Apr 1;65(3):1-23. [PMID: 27031587] disorders. Neuron. 2012 Dec 20;76(6):1052-6. [PMID: 23259942] 9. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, Kim YK, Lee H, Song DH, 4. Werling DM, Parikshak NN, Geschwind DH. Gene Grinker RR. Prevalence of autism spectrum disorders expression in human brain implicates sexually in a total population sample. Am J Psychiatry. 2011 dimorphic pathways in autism spectrum disorders. Sep;168(9):904-12. [PMID: 21558103] Nat Commun. 2016 Feb 19;7:10717. [PMID: 26892004]

5. Werling DM. The role of sex-differential biology in risk for autism spectrum disorder. Biol Sex Differ. 2016 Nov 16;7:58. eCollection 2016. [PMID: 27891212]

6. Brugha T, McManus S, Meltzer H, Smith J, Scott FJ, Purdon S, Harris J, Bankart J. Autism Spectrum Disorders in Adults Living in Households Throughout England—Report From the Adult Psychiatric Morbidity Survey 2007. Leeds, England NHS Information Centre. 2009. http://content.digital. nhs.uk/pubs/asdpsychiatricmorbidity07

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BUDGET RECOMMENDATiON

1. Buescher AV, Cidav Z, Knapp M, Mandell DS. 6. Cidav Z, Munson J, Estes A, Dawson G, Rogers S, Costs of autism spectrum disorders in the United Mandell D. Cost Offset Associated with Early Start Kingdom and the United States. JAMA Pediatr. Denver Model for Children with Autism. J Am Acad 2014 Aug;168(8):721-8. [PMID: 24911948] Child Adolesc Psychiatry. [Available online 4 July 2017: http://www.sciencedirect.com/science/article/ 2. Lavelle TA, Weinstein MC, Newhouse JP, Munir K, pii/S0890856717303131?via%3Dihub] Kuhlthau KA, Prosser LA. Economic burden of childhood autism spectrum disorders. Pediatrics. 7. Roux AM, Shattuck PT, Rast JE, Rava JA, Anderson 2014 Mar;133(3):e520-9. [PMID: 24515505] KA. National Autism Indicators Report: Transition into young adulthood. Philadelphia, PA: Life Course 3. Leigh JP, Du J. Brief Report: Forecasting the economic Outcomes Research Program, A.J. Drexel Autism burden of autism in 2015 and 2025 in the United Institute, Drexel University, 2015. [http://drexel.edu/ States. J Autism Dev Disord. 2015 Dec;45(12):4135-9. autismoutcomes/publications-and-reports/ [PMID: 26183723] publications/National-Autism-Indicators-Report- Transition-to-Adulthood/#sthash.IhJf7Y5P.dpbs] 4. Peters-Scheffer N, Didden R, Korzilius H, Matson J. Cost comparison of early intensive behavioral 8. Järbrink K, McCrone P, Fombonne E, Zandén intervention and treatment as usual for children H, Knapp M. Cost-impact of young adults with with autism spectrum disorder in The Netherlands. high-functioning autistic spectrum disorder. Res Dev Disabil. 2012 Nov-Dec;33(6):1763-72. Res Dev Disabil. 2007 Jan-Feb;28(1):94-104. [PMID: 22705454] [PMID: 16551499]

5. Penner M, Rayar M, Bashir N, Roberts SW, 9. https://officeofbudget.od.nih.gov/pdfs/FY18/ Hancock-Howard RL, Coyte PC. Cost-effectiveness BRDPI%20Table%20FY%201950%20to% analysis comparing pre-diagnosis autism spectrum 202022_Jan%202017.pdf disorder (ASD)-targeted intervention with Ontario's Autism Intervention Program. J Autism Dev Disord. 2015 Sep;45(9):2833-47. [PMID: 25936527]

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INTERAGENCY AUTISM COORDINATING COMMITTEE MEMBER ROSTER

CHAiR

Joshua Gordon, M.D., Ph.D. Director National Institute of Mental Health National Institutes of Health Rockville, MD

FEDERAL MEMBERS Ruth Etzel, M.D., Ph.D. Director James F. Battey, M.D., Ph.D. Office of Children’s Health Protection Director Environmental Protection Agency National Institute on Deafness and Other Washington, DC Communication Disorders National Institutes of Health Tiffany R. Farchione, M.D. Bethesda, MD Medical Officer Division of Psychiatry Products Diana W. Bianchi, M.D. Center for Drug Evaluation and Research Director U.S. Food and Drug Administration Eunice Kennedy Shriver National Institute of Silver Spring, MD Child Health and Human Development National Institutes of Health Melissa L. Harris Bethesda, MD Acting Deputy Director Disabled and Elderly Health Programs Group Linda Birnbaum, Ph.D., D.A.B.T., A.T.S. Centers for Medicare and CHIP Services Director Centers for Medicare and Medicaid Services National Institute of Environmental Health Baltimore, MD Sciences and National Toxicology Program National Institutes of Health Laura Kavanagh, M.P.P. Research Triangle Park, NC Director Division of Research, Training and Education Francis S. Collins, M.D., Ph.D. Maternal and Child Health Director Health Resources and Services Administration National Institutes of Health Rockville, MD Bethesda, MD

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Walter J. Koroshetz, M.D. Melissa Spencer Deputy Director Deputy Associate Commissioner National Institute of Neurological Disorders Office of Disability Policy and Stroke Social Security Administration National Institutes of Health Baltimore, MD Bethesda, MD Larry Wexler, Ed.D. Laura Pincock, Pharm.D., M.P.H. Director Pharmacist Officer Research to Practice Agency for Healthcare Research and Quality Office of Special Education Programs Rockville, MD U.S. Department of Education Washington, DC Marcella Ronyak, Ph.D., L.C.S.W., C.D.P. Deputy Director Nicole M. Williams, Ph.D. Division of Behavioral Health Program Manager Indian Health Service Headquarters Congressionally Directed Medical Research Programs Stuart K. Shapira, M.D., Ph.D. U.S. Department of Defense Associate Director Frederick, MD Science and Chief Medical Officer National Center on Birth Defects and Developmental Disabilities Atlanta, GA

PUBLiC MEMBERS

David Amaral, Ph.D. Samantha Crane, J.D. Distinguished Professor Legal Director and Director of Public Policy Department of Psychiatry & Behavioral Science Autistic Self Advocacy Network University of California, Davis (UC) Washington, DC Research Director UC Davis MIND Institute Geraldine Dawson, Ph.D. University of California – Davis Professor Sacramento, CA Department of Psychiatry and Behavioral Science Medical Center James Ball, Ed.D., B.C.B.A.-D. Director President and CEO Duke Center for Autism and Brain Development JB Autism Consulting President Executive Chair, Board of Directors International Society for Autism Research Autism Society Durham, NC Cranbury, NJ

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Amy Goodman, M.A. Edlyn Peña, Ph.D. Self-Advocate Associate Professor, Educational Leadership Charles Town, WV and Director of Doctoral Studies California Lutheran University Shannon Haworth, M.A. Thousand Oaks, CA Senior Program Manager Association of University Centers on Disabilities Louis Reichardt, Ph.D. Silver Spring, MD Director Simons Foundation Autism Research Initiative David S. Mandell, Sc.D. New York, NY Director Center for Mental Health Policy Robert H. Ring, Ph.D. and Services Research Chief Executive Officer Associate Professor Vencerx Therapeutics Psychiatry and Pediatrics Princeton, NJ Perelman School of Medicine University of Pennsylvania John Elder Robison Philadelphia, PA Self-Advocate, Parent, and Author Amherst, MA Brian Parnell, M.S.W. Administrator, Medicaid Autism Waiver Alison Tepper Singer, M.B.A. & Community Supports Waiver Parent and Family Member Division of Services for People with Disabilities Founder and President Utah Department of Human Services Autism Science Foundation Draper, UT New York, NY

Kevin Pelphrey, Ph.D. Julie Lounds Taylor, Ph.D. Carbonell Family Professor in Autism Assistant Professor of Pediatrics and Neurodevelopmental Disorders and Special Education Professor in the Department of Pharmacology Vanderbilt University Investigator, Vanderbilt and Physiology and Department of Pediatrics Kennedy Center Director, Autism and Neurodevelopmental Nashville, TN Disorders Institute George Washington University and Children's National Medical Center Washington, DC

165 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

iACC ALTERNATES

Josie Briggs, M.D. Cindy Lawler, Ph.D. (for Francis S. Collins, M.D., Ph.D.) (for Linda Birnbaum, Ph.D., D.A.B.T., A.T.S.) Director, National Center for Complementary Chief, Genes, Environment and Health Branch and Integrative Health National Institute of Environmental Health Sciences National Institutes of Health National Institutes of Health Bethesda, MD Research Triangle Park, NC

Deborah (Daisy) Christensen, Ph.D. Laura Mamounas, Ph.D. (for Stuart K. Shapira, M.D., Ph.D.) (for Walter Koroshetz, M.D.) Epidemiologist, Surveillance Team Lead Program Director, Neurogenetics Cluster Developmental Disabilities Branch National institute of Neurological Disorders National Center on Birth Defects and Stroke and Developmental Disabilities Bethesda, MD Centers for Disease Control and Prevention Atlanta, GA Shui-Lin (Stan) Niu, Ph.D. (for Nicole Williams, Ph.D.) Judith A. Cooper, Ph.D. Science Officer, Congressionally Directed (for James F. Battey, M.D., Ph.D.) Medical Research Programs Deputy Director, National Institute on Deafness U.S. Department of Defense and Other Communication Disorders Frederick, MD Director, Division of Scientific Programs National Institutes of Health Robyn Schulhof, M.A. Bethesda, MD (for Laura Kavanagh, M.P.P.) Senior Public Health Analyst, Maternal Jennifer Johnson, Ed.D. and Child Health Bureau (for Administration for Community Living) Health Resources and Services Administration Deputy Director, Administration on Intellectual Rockville, MD and Developmental Disabilities Administration for Community Living Washington, DC

Alice Kau, Ph.D. (for Diana W. Bianchi, M.D.) Program Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda, MD

166 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

STRATEGIC PLAN WORKING GROUP MEMBERS

The Committee would like to thank the following individuals who volunteered their time to assist with the development of the 2016-2017 IACC Strategic Plan for ASD.

QUESTiON 1 WORKiNG GROUP

CO-CHAiRS

Alice Kau, Ph.D* Ann E. Wagner, Ph.D Health Scientist Administrator Program Chief Eunice Kennedy Shriver National Institute of Neurobehavioral Mechanisms of Child Health and Human Development Mental Disorders Branch National Institutes of Health Division of Developmental Translational Research Bethesda, MD National Institute of Mental Health National Institutes of Health Bethesda, MD

PARTiCiPANTS

Daniel Coury, M.D. Jennifer Johnson, Ed.D.* Section Chief Deputy Director Behavioral Health Services Administration on Intellectual and Section Chief Developmental Disabilities Child Development Center Administration for Community Living Physician Team Washington, DC Developmental and Behavioral Pediatrics Program Director Ami Klin, Ph.D. Developmental/Behavioral Pediatrics Fellowship Director Nationwide Children’s Hospital Marcus Autism Center Columbus, OH Children's Healthcare of Atlanta Georgia Research Alliance Eminent Scholar Shannon Haworth, M.A. Professor & Chief Senior Program Manager Division of Autism and Related Disorders Association of University Centers on Disabilities Department of Pediatrics Silver Spring, MD Emory University School of Medicine Center for Translational Social Neuroscience Emory University Atlanta, GA

167 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Catherine Lord, Ph.D. Audrey Thurm, Ph.D. Professor of Psychology Staff Scientist Psychiatry and Founding Director Pediatrics and Developmental Neuroscience Center for Autism and Developing Brain National Institute of Mental Health New York-Presbyterian Hospital National Institutes of Health Weill Cornell Medical College Bethesda, MD New York, NY Debra Wagler, M.A., MComm. Sandy Magaña, Ph.D., M.S.W. Public Health Analyst Professor Region VIII University of Illinois at Chicago Maternal and Child Health Bureau Department of Disability and Human Development Health Resources and Services Administration Chicago, IL Rockville, MD

Karen Pierce, Ph.D. Amy M. Wetherby, Ph.D. Associate Professor Dept. of Clinical Sciences Department of Neurosciences College of Medicine Co-Director Distinguished Research Professor Autism Center L.L. Schendel Professor of Communication Science University of California – San Diego & Disorders La Jolla, CA Florida State University Tallahassee, FL Diana L. Robins, Ph.D. Associate Professor Lisa D. Wiggins, Ph.D. Program Area Leader in Early Detection Epidemiologist & Intervention National Center on Birth Defects AJ Drexel Autism Institute and Developmental Disabilities Drexel University Centers for Disease Control and Prevention Philadelphia, PA Atlanta, GA

Angela Scarpa, Ph.D. Nicole Williams, Ph.D.* Founder and Co-Director Program Manager VT Autism Clinic (VTAC) Congressionally Directed Medical Research Programs Director U.S. Department of Defense VT Center for Autism Research (VTCAR) Frederick, MD Associate Professor Department of Psychology Virginia Tech Blacksburg, VA

*indicates IACC Member

168 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

QUESTiON 2 WORKiNG GROUP

CO-CHAiRS

Walter Koroshetz, M.D.* Louis Reichardt, Ph.D.* Director Director National Institute of Neurological Disorders Simons Foundation Autism Research Initiative and Stroke New York, NY National Institutes of Health Bethesda, MD

PARTiCiPANTS

David Amaral, Ph.D.* Guoping Feng, Ph.D. Distinguished Professor Poitras Professor of Neuroscience Department of Psychiatry & Behavioral Sciences McGovern Institute for Brain Research Research Director Department of Brain and Cognitive Sciences UC Davis MIND Institute Massachusetts Institute of Technology University of California – Davis Director of Model Systems and Neurobiology Sacramento, CA Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard James F. Battey, M.D., Ph.D.* Cambridge, MA Director National Institute on Deafness Heather Cody Hazlett, Ph.D. and Other Communication Disorders Assistant Professor National Institutes of Health The University of North Carolina Bethesda, MD Chapel Hill, NC

Katarzyna Chawarska, Ph.D. Shafali Spurling Jeste, M.D. Associate Professor Associate Professor in Psychiatry and Neurology Child Study Center and Pediatrics University of California – Los Angeles Temple Medical Center David Geffen School of Medicine New Haven, CT Los Angeles, CA

Graeme Davis, Ph.D. Eric Klann, Ph.D. Professor Professor Neuroscience Graduate Program Center for Neural Science University of California – San Francisco New York University San Francisco, CA New York, NY

169 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

James McPartland, Ph.D. Elizabeth Redcay, Ph.D. Associate Professor of Child Psychiatry Assistant Professor of Psychology and Psychology Director Director Developmental Social Neuroscience Lab Yale Developmental Disabilities Clinic University of Maryland College Park, MD New Haven, CT Robert H. Ring, Ph.D.* Christine Nordahl, Ph.D. Chief Executive Officer Assistant Professor Vencerx Therapeutics Department of Psychiatry and Princeton, NJ Behavioral Science UC Davis MIND Institute Flora Vaccarino, M.D. University of California – Davis Harris Professor Sacramento, CA Child Study Center and Department of Neurobiology Kevin Pelphrey, Ph.D.* Yale University Carbonell Family Professor in Autism New Haven, CT and Neurodevelopmental Disorders Professor in the Department of Pharmacology Nicole Williams, Ph.D.* and Physiology and Department of Pediatrics Program Manager Director, Autism and Neurodevelopmental Congressionally Directed Medical Research Programs Disorders Institute U.S. Department of Defense George Washington University Frederick, MD and Children's National Medical Center Washington, DC

QUESTiON 3 WORKiNG GROUP

CO-CHAiRS

David Amaral, Ph.D.* Cindy Lawler, Ph.D. Distinguished Professor Chief Department of Psychiatry & Behavioral Sciences Genes, Environment and Health Branch Research Director National Institute of Environmental Health Sciences UC Davis MIND Institute National Institutes of Health University of California – Davis Research Triangle Park, NC Sacramento, CA

*indicates IACC Member

170 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

PARTiCiPANTS

Raphael Bernier, Ph.D. Irva Hertz-Picciotto, Ph.D. Associate Professor Director Department of Psychiatry & Behavioral Sciences UC Davis Environmental Health Sciences Core Center Clinical Director Professor & Vice Chair for Research Seattle Children's Autism Center Department of Public Health Sciences Associate Director Director Center on Human Development and Disability MIND Institute Program in Environmental University of Washington Epidemiology of Autism and Neurodevelopment Seattle, WA Co-Executive Director Project TENDR (Targeting Environmental Evan Eichler, Ph.D. NeuroDevelopment Risks) Professor and HHMI Investigator University of California – Davis University of Washington Davis, CA Seattle, WA Elaine Hsiao, Ph.D. Ruth Etzel, M.D., Ph.D.* Professor Director Life Science, Integrative Biology and Physiology Office of Children’s Health Protection University of California Office of Environmental Protection Agency Los Angeles, CA Environmental Protection Agency Washington, DC Craig Newschaffer, Ph.D. Professor Dani Fallin, Ph.D. Director Professor A.J. Drexel Autism Institute Bloomberg School of Public Health Philadelphia, PA John Hopkins University Baltimore, MD Elise Robinson, Ph.D. Affiliated Scientist Daniel Geschwind, Ph.D. Broad Institute Senior Associate Dean Cambridge, MA Associate Vice Chancellor Precision Medicine Stephan Sanders, Ph.D. University of California – Los Angeles Assistant Professor Los Angeles, CA Psychiatry UCSF School of Medicine Alycia Halladay, Ph.D. University of California – San Francisco Chief Science Officer San Francisco, CA Autism Science Foundation New York, NY

171 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Steve Scherer, Ph.D, F.R.S.C. Joan A. Scott, M.S., C.G.C. Director Deputy Director The Centre for Applied Genomics Division of Services for Children with Special Health Needs Senior Scientist, Health Resources and Services Administration Genetics & Genomic Biology Maternal and Child Health Bureau The Hospital for Sick Children Rockville, MD Director McLaughlin Centre for Molecular Medicine Alison Tepper Singer, M.B.A.* Professor President Department of Molecular Genetics Autism Science Foundation University of Toronto New York, NY Toronto, Canada

Laura A. Schieve, Ph.D. Team Lead Epidemiology Team Developmental Disabilities Branch Division of Congenital and Developmental Disorders National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention Atlanta, GA

QUESTiON 4 WORKiNG GROUP

CHAiR

Kevin Pelphrey, Ph.D.* Carbonell Family Professor Autism and Neurodevelopmental Disorders Professor Department of Pharmacology and Physiology and Department of Pediatrics Director Autism and Neurodevelopmental Disorders Institute George Washington University and Children's National Medical Center Washington, DC

*indicates IACC Member

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PARTiCiPANTS

James Ball, Ed.D.* Connie Kasari, Ph.D. President and CEO Professor JB Autism Consulting Psychological Studies Cranbury, NJ Education and Psychiatry University of California - Los Angeles Timothy Buie, M.D. Los Angeles, CA Director Gastroenterology and Nutation Elisabeth Kato* at the Laure Center for Autism Medical Officer Massachusetts General Hospital Agency for Healthcare Research and Quality Boston, MA Rockville, MD

Samantha Crane, J.D.* Alice Kau, Ph.D* Legal Director and Director of Public Policy Health Scientist Administrator Autistic Self Advocacy Network Eunice Kennedy Shriver National Institute of Washington, DC Child Health and Human Development National Institutes of Health Geraldine Dawson, Ph.D.* Bethesda, MD Professor Department of Psychiatry and Christy Kavulic Behavioral Science Associate Division Director Duke University School of Medicine Early Childhood Team Director Office of Special Education Program Duke Center for Autism and U.S. Department of Education Brain Development Washington, DC President International Society for Autism Research Alex Kolevzon, M.D. Durham, NC Professor of Psychiatry and Pediatrics Director Tiffany R. Farchione, M.D.* Child and Adolescent Psychiatry Deputy Director Clinical Director Division of Psychiatry Products Seaver Autism Center Center for Drug Evaluation and Research Icahn School of Medicine at Mounttn Sinai US Food and Drug Administration New York, NY Silver Spring, MD Elizabeth Laugeson, Ph.D. Melissa L. Harris* Director Acting Deputy Director Early Childhood Clubhouse Program Disabled and Elderly Health Programs Group Clinical Instructor Center for Medicare and CHIP Services Center for Autism Research and Treatment Centers for Medicare and Medicaid Services David Geffen School of Medicine Baltimore, MD Los Angeles, CA

173 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Alexander Leonessa Frederick Shic, Ph.D. National Science Foundation Assistant Professor Arlington, Virginia Child Study Center and Computer Science Director Beth Malow, M.D. Technology and Innovation Laboratory Professor Associate Director Vanderbilt Department of Neurology Yale Early Social Cognition Lab Vanderbilt University Medical Center Yale Child Study Center Nashville, TN Yale School of Medicine New Haven, CT Nancy J. Minshew, M.D. Endowed Chair in Autism Research Phillip S. Strain, Ph.D. Professor of Psychiatry and Neurology Director Department of Psychiatry PELE Center/Professor University of Pittsburgh ED. Psych & Early Childhood SPED Pittsburgh, PA University of – Denver Denver, CO Samuel L. Odom, Ph.D. Director Denis G. Sukhodolsky, Ph.D. Frank Porter Graham Child Development Institute Assistant Professor University of North Carolina at Chapel Hill Child Study Center Chapel Hill, NC Yale School of Medicine New Haven, CT Louis Reichardt, Ph.D.* Director Zachary Warren, Ph.D. Simons Foundation Autism Research Initiative Associate Professor of Pediatrics, Psychiatry, New York, NY & Special Education Executive Director Robert H. Ring, Ph.D.* Treatment and Research Institute for Chief Executive Officer Autism Spectrum Disorders Vencerx Therapeutics Director Princeton, NJ Autism Clinical Services Department of Pediatrics and Vanderbilt Mustafa Sahin, M.D., Ph.D. Kennedy Center Associate Professor of Neurology Nashville, TN Harvard Medical School Assistant in Neurology Boston Children’s Hospital Boston, MA

*indicates IACC Member

174 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

QUESTiON 5 WORKiNG GROUP

CO-CHAiRS

Shannon Haworth, M.A. David S. Mandell, Sc.D.* Senior Program Manager Director Association of University Centers on Disabilities Center for Mental Health Policy and Services Research Silver Spring, MD Associate Professor Psychiatry and Pediatrics Perelman School of Medicine University of Pennsylvania Philadelphia, PA

PARTiCiPANTS

Lauren Brookman-Frazee, Ph.D. Melissa L. Harris* Associate Professor Acting Deputy Director Department of Psychiatry Disabled and Elderly Health Programs Group University of California – San Diego Center for Medicare and CHIP Services San Diego, CA Centers for Medicare and Medicaid Services Baltimore, MD Robert Cimera, Ph.D. Professor Peter F. Gerhardt, Ed.D. Lifespan Development & Educational Science President Kent State University Peter Gerhardt Associates, LLC Kent, OH New York, NY

Samantha Crane, J.D.* Lisa Goring Legal Director and Director of Public Policy Executive Vice President Autistic Self Advocacy Network Programs and Services Washington, DC Autism Speaks New York, NY Daniel Davis Health Insurance Specialist Laura Kavanagh, M.P.P.* Center for Integrated Programs Deputy Associate Administrator Administration for Community Living Maternal and Child Health Bureau U.S. Department of Health and Human Services Health Resources and Services Administration Washington, DC Rockville, MD

175 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Leticia Manning, M.P.H. Jane A. Tilly Lieutenant Commander Administration for Community Living United States Public Health Service Administration on Aging Maternal and Child Health Bureau U.S. Department of Health and Human Services Division of Services for Children with Washington, DC Special Health Needs Health Resources and Services Administration Larry Wexler, Ed.D.* Rockville, MD Director Research to Practice Division Cathy Pratt, Ph.D., BCBA-D Office of Special Education Programs Director U.S. Department of Education Indiana Resource Center for Autism Washington, DC Indiana University Bloomington Bloomington, IN Juliann Woods, Ph.D., CCC-SLP Professor and Associate Dean Anne Roux, M.P.H. Research School of Communication Science Research Scientist and Disorders Life Course Outcomes Florida State University Research Program Tallahassee, FL A.J. Drexel Autism Institute Drexel University Philadelphia, PA

Aubyn Stahmer, Ph.D. Associate Professor Psychiatry and Behavioral Sciences UC Davis MIND Institute University of California – Davis Sacramento, CA

QUESTiON 6 WORKiNG GROUP

CHAiR

Julie Lounds Taylor, Ph.D.* Assistant Professor of Pediatrics and Special Education

Vanderbilt University

Investigator

Vanderbilt Kennedy Center *indicates IACC Member Nashville, TN

176 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

PARTiCiPANTS

Scott Badesch Amy Goodman, M.A.* President/Chief Executive Officer Self-Advocate Autism Society Bethesda, MD Laura Grofer Klinger, Ph.D. Director Vanessa Hus Bal, Ph.D. TEACCH Autism Program Postdoctoral Scholar Associate Professor of Psychiatry Department of Psychiatry University of North Carolina – Chapel Hill University of California - San Francisco Chapel Hill, NC San Francisco, CA Kevin Pelphrey, Ph.D.* Somer L. Bishop, Ph.D. Carbonell Family Professor Assistant Professor Autism and Neurodevelopmental Disorders Department of Psychiatry Professor in the Department of Pharmacology University of California - San Francisco and Physiology and Department of Pediatrics San Francisco, CA Director Autism and Neurodevelopmental Disorders Institute Leslie J. Caplan, Ph.D. George Washington University and Rehabilitation Program Specialist Children's National Medical Center National Institute on Disability, Independent Living, Washington, DC and Rehabilitation Research Administration for Community Living Edlyn Peña, Ph.D.* U.S. Department of Health and Human Services Associate Professor Washington, DC Educational Leadership Director of Doctoral Studies Nancy Cheak-Zamora, Ph.D. California Lutheran University Assistant Professor Thousand Oaks, CA Department of Health Science University of Missouri School of Health Professions JaLynn Prince Columbia, MO President and Founder Madison House Autism Foundation Samantha Crane, J.D.* Rockville, MD Legal Director and Director of Public Policy Autistic Self Advocacy Network Robyn Schulhof, M.A.* Washington, DC Senior Public Health Analyst Maternal and Child Health Bureau Leann Smith DaWalt, Ph.D. Health Resources and Services Administration Senior Scientist Rockville, MD Waisman Center University of Wisconsin – Madison Madison, WI

177 2016-2017 IACC STRATEGIC PLAN FOR AUTISM SPECTRUM DISORDER

Paul Shattuck, Ph.D. Susan White, Ph.D. Associate Professor Faculty Leader – Life Course Outcomes Research Program Department of Psychology A.J. Drexel Autism Institute Core Faculty Philadelphia, PA Clinical Science Co-Director Alison Tepper Singer, M.B.A.* Virginia Tech Autism Clinic President Virginia Tech Autism Science Foundation Blacksburg, VA New York, NY

QUESTiON 7 WORKiNG GROUP

CHAiR

Alison Tepper Singer, M.B.A.* President Autism Science Foundation New York, NY

PARTiCiPANTS

Deborah (Daisy) Christensen, Ph.D.* Maureen Durkin, Ph.D., DrPH Epidemiologist Professor Surveillance Team Lead Population Health Sciences and Pediatrics Developmental Disabilities Branch University of Wisconsin School of Medicine National Center on and and Public Health Developmental Disabilities Professor Centers for Disease Control and Prevention Population Health Sciences and Pediatrics Atlanta, GA Vice-Chair Department of Population Health Sciences Samantha Crane, J.D.* Director Legal Director and Director of Public Policy Population Health Graduate Program Autistic Self Advocacy Network University of Wisconsin School of Medicine Washington, DC and Public Health Madison, WI Adriana DiMartino, Ph.D. Assistant Professor Department of Child and Adolescent Psychiatry New York University School of Medicine New York, NY

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Michelle Freund, Ph.D. Gretchen Navidi Project Officer Program Coordination Manager National Institute of Mental Health Office of Technology Development and Coordination National institute of Health Office of the NIMH Director Rockville, MD National Institute of Mental Health National Institutes of Health Dan Hall Bethesda, MD Manager National Database for Autism Research Jessica Rast, M.P.H. National Institute of Mental Health Research Associate National Institutes of Health Life Course Outcomes Research Program Rockville, MD A.J. Drexel Autism Institute Drexel University Robin L. Harwood, Ph.D. Philadelphia, PA Health Scientist Division of Research Catherine Rice, Ph.D. Office of Epidemiology and Research Professor Health Resources and Services Administration Psychiatry and Behavioral Sciences Maternal and Child Health Bureau Director, Emory Autism Center Rockville, MD Emory University School of Medicine Atlanta, GA Paul Lipkin, M.D. Director Robert H. Ring, Ph.D.* Medical Informatics Chief Executive Officer Kennedy Krieger Institute Vencerx Therapeutics Director Princeton, NJ Interactive Autism Network Kennedy Krieger Institute Michael Rosanoff, M.P.H. Associate Professor of Pediatrics Director Johns Hopkins Medicine Public Health Research Baltimore, MD Autism Speaks New York, NY David S. Mandell, Sc.D.* Director Andy Shih, Ph.D. Center for Mental Health Policy and Senior VP Services Research Scientific Affairs Associate Professor Autism Speaks Psychiatry and Pediatrics New York, NY Perelman School of Medicine University of Pennsylvania Philadelphia, PA

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OFFICE OF AUTISM RESEARCH COORDINATION (OARC)

National Institute of Mental Health, National Institutes of Health

Susan A. Daniels, Ph.D. Director

Oni Celestin, Ph.D. Karen Mowrer, Ph.D. Health Science Policy Analyst Health Science Policy Analyst

Rebecca Martin, M.P.H. Julianna Rava, M.P.H. Public Health Analyst Health Science Policy Analyst

Angelice Mitrakas, B.A. Jeffrey Wiegand, B.S. Management Analyst Web Development Manager

Email: [email protected] Website: http://www.iacc.hhs.gov

180 U.S. Department of Health and Human Services www.hhs.gov